Mapping Heterogeneity of Hepatocellular Carcinoma by Investigating Hepatocyte-Specific Genes/TFs/Pathways Across Cellular and Tumor Landscapes

Mapping Heterogeneity of Hepatocellular Carcinoma by Investigating Hepatocyte-Specific Genes/TFs/Pathways Across Cellular and Tumor Landscapes | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Mapping Heterogeneity of Hepatocellular Carcinoma by Investigating Hepatocyte-Specific Genes/TFs/Pathways Across Cellular and Tumor Landscapes Ovais Shafi, Rahimeen Rajpar, Shakaib Zafar, Saba Irfan, Muhammad Ashar, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4360926/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Hepatocellular carcinoma (HCC) presents challenges due to tumor heterogeneity and therapeutic resistance. Understanding the molecular mechanisms driving heterogeneity is crucial. Key transcription factors (HNF4A, HNF1A, FOXA1/2, etc.) and signaling pathways (Wnt/β-catenin, FGF, HGF, etc.) are dysregulated in HCC. Dysregulation disrupts hepatocyte genetic programming, leading to heterogeneous cell populations. Investigating these mechanisms offers insights for targeted therapies and improving patient outcomes in HCC. Methods: Databases, including PubMed, MEDLINE, Google Scholar, and open access/ subscription-based journals were searched for published articles without any date restrictions, to trace the emergence of HCC heterogeneity by investigating the hepatocyte-specific genes/TFs/signaling pathways across cellular and tumor landscapes. Based on the criteria mentioned in the methods section, studies were systematically reviewed to investigate HCC Heterogeneity. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Results: This study into hepatocellular carcinoma (HCC) revealed dysregulation of key transcription factors (TFs) and signaling pathways. Transcription factors HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, HNF6/Onecut1, and ONECUT2/HNF6β showed altered expression patterns, disrupting hepatocyte genetic programming and promoting heterogeneous cell populations in HCC. Dysregulated Wnt/β-catenin, FGF, HGF, TGF-β, and Hippo signaling pathways influenced cellular fate decisions and interactions with the tumor microenvironment, further contributing to HCC heterogeneity. Dysregulated NOTCH signaling and TBX3/18 transcription factors highlighted the complexity of HCC heterogeneity. This study points to the critical role of dysregulated TFs and signaling pathways in driving HCC heterogeneity and transdifferentiation, providing insights for targeted therapeutic interventions to improve patient outcomes. Conclusion: The decline in the gene expression of hepatocyte cell type-specific genes dysregulates the genetic programing of hepatocytes involved in cell type-specific homeostasis. The multiple roles of every gene/TF begin to manifest themselves causing the emergence of heterogeneity. The dysregulation of hepatocyte-specific genes and signaling pathways in hepatocellular carcinoma (HCC) disrupts cellular homeostasis, leading to the emergence of heterogeneity and transdifferentiation. Key transcription factors like HNF4A, HNF1A, and FOXA1/2, along with pathways such as Wnt/β-catenin and Hippo signaling, play crucial roles. This disruption sets the stage for diverse cellular phenotypes within the tumor microenvironment. Understanding these molecular mechanisms is vital for developing targeted therapeutic strategies to address HCC heterogeneity and improve patient outcomes. Gastroenterology & Hepatology Oncology Stem Cell & Developmental Cell Biology Medical Genetics Hepatocellular carcinoma Heterogeneity Transdifferentiation Hepatocyte-specific genes Transcription factors Signaling pathways Tumor microenvironment Therapeutic targets Figures Figure 1 Background Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal forms of cancer worldwide, representing a significant public health burden. Despite advances in treatment modalities, the prognosis for patients with HCC remains poor, largely due to tumor heterogeneity and therapeutic resistance [ 1 ]. HCC tumors exhibit remarkable diversity in cellular phenotypes, molecular profiles, and therapeutic responses, posing significant challenges for effective clinical management. Understanding the molecular mechanisms driving the emergence of HCC heterogeneity and transdifferentiation is crucial for improving patient outcomes and developing targeted therapeutic strategies [ 2 ]. A comprehensive investigation into the dysregulated expression of key transcription factors, signaling pathways, and developmental regulators implicated in HCC pathogenesis is essential for elucidating the complex molecular landscape of HCC tumors. Transcription factors such as HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, HNF6/Onecut1, and ONECUT2/HNF6β play critical roles in hepatocyte development and differentiation. Dysregulation of these transcription factors disrupts the genetic programming of hepatocytes, leading to the emergence of heterogeneous cell populations within HCC tumors. Additionally, signaling pathways such as the Wnt/β-catenin pathway, fibroblast growth factor (FGF) signaling, hepatocyte growth factor (HGF) signaling, transforming growth factor-beta (TGF-β) signaling, and the Hippo signaling pathway are frequently dysregulated in HCC. Activation or inhibition of these pathways influences cellular fate decisions, promotes stemness, and modulates interactions with the tumor microenvironment, contributing to the heterogeneity observed in HCC. By investigating the dysregulated expression of these key regulators and signaling pathways, we can gain valuable insights into the molecular mechanisms driving HCC heterogeneity and transdifferentiation [ 5 , 6 ]. Hepatocellular carcinoma (HCC) is characterized by significant heterogeneity, both at the cellular and molecular levels, which poses challenges for effective diagnosis and treatment. This study aims to investigate the mechanisms underlying the emergence of heterogeneity and transdifferentiation in HCC, drawing upon recent findings from research in developmental biology, genetics, and tumor biology [ 9 ]. Key pathways and transcriptional factors implicated in HCC heterogeneity and transdifferentiation are discussed, along with their roles in normal hepatocyte development and other tumors. Insights into the dysregulation of these pathways and factors shed light on the cellular plasticity and phenotypic diversity observed in HCC. Understanding the molecular underpinnings of HCC heterogeneity is crucial for developing targeted therapeutic approaches that can effectively combat this deadly disease [ 10 , 11 ]. Methods PUBMED database, MEDLINE database, Google Scholar and open access/ subscription-based journals were searched with no date restrictions for published articles. The following key genes/ transcription factors/ signaling pathways involved in the proliferation and differentiation of hepatocytes were investigated for their expression in other cell-types, presence or role in other tumors, and for dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6β, TBX3/18, Wnt/β-catenin pathway, FGF, HGF, TGF-β, Hippo signaling pathway. The primary objective of this study is to trace the emergence of heterogeneity in HCC. The ultimate goal is to provide valuable insights into the HCC heterogeneity that in future may lead to potential future therapeutic targets for improved clinical management of patients with HCC. Screening of the literature was also done on this same basis and related data was extracted. Literature search began in August 2020 and ended in November 2023. An in-depth investigation was conducted during this duration based on the parameters of the study as defined above. During revision, further literature was searched and referenced until March 2024. The literature search and all sections of the manuscript were checked multiple times during the months of revision (December 2023 – March 2024) to maintain the highest accuracy possible. The prime focus of the literature search was to screen the literature on the basis of eligibility criteria mentioned above. It employs PRISMA guidelines as a tool for the investigation. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Publications only in ‘English’ were used and there was no limitation on date of publication. Data extraction was based on these eligibility criteria. Studies were systematically reviewed based on the criteria mentioned in the methods section. No unpublished study was used or included. Results A total of 3066 articles were identified using database searching, and 2952 were recorded after duplicates removal. 2626 were excluded after screening of title/abstract, 51 were finally excluded, and 5 articles were excluded during data extraction. Finally, 270 articles were included as references. Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, typically arises from hepatocytes, the primary liver cell type responsible for crucial functions such as metabolism, protein synthesis, and detoxification [ 1 ]. When hepatocytes undergo genetic mutations or other alterations triggering uncontrolled growth, they can progress into hepatocellular carcinoma. Moreover, HCC can originate from progenitor cells or stem cells within the liver. The cell type-specific genetic architecture for hepatocytes encompasses a specific amalgamation of genes, transcription factors, and signaling pathways that precisely regulate their development, differentiation, and function [ 2 , 3 ]. Key components integral to the developmental biology of hepatocytes include a range of genes such as HNF4A, HNF1A, FOXA1, FOXA2, CEBPA, GATA4, GATA6, PROX1, SOX9, NOTCH2, HNF6, Onecut1, Onecut2, TBX3, and TBX18, along with associated signaling pathways like the Notch, Wnt/β-catenin, FGF, HGF/c-Met, TGF-β, and Hippo pathways [ 4 ]. These elements interact synergistically, orchestrating the specification, differentiation, and maturation of hepatocytes throughout development. Together, they constitute a regulatory network governing hepatocyte fate and function, essential for ensuring proper liver development and homeostasis. Disruption of this genetic architecture can result in developmental abnormalities or liver pathologies, highlighting its critical role in maintaining liver health and function [ 5 , 6 ]. Tumor heterogeneity in hepatocellular carcinoma: Hepatocellular carcinoma (HCC) presents considerable variability among patients concerning its etiology, molecular characteristics, and clinical outcomes. Despite progress in genomic profiling pinpointing molecular subtypes of HCC, the precise contributors to this heterogeneity remain incompletely understood [ 7 ]. Delving deeper into the genetic, epigenetic, and microenvironmental factors influencing HCC heterogeneity holds promise for enhancing patient stratification and tailoring personalized treatment approaches. Although certain genetic mutations like TP53 and CTNNB1 (β-catenin) alterations are prevalent in HCC, the disease also demonstrates significant molecular diversity. Various molecular subtypes of HCC have been delineated based on disparate gene expression patterns, activation of signaling pathways, and genomic changes. This diversity complicates the development of targeted therapies and individualized treatment strategies, necessitating a more comprehensive understanding of HCC's molecular landscape for improved therapeutic outcomes [ 8 ]. Tumor heterogeneity within hepatocellular carcinoma (HCC) encompasses diverse cellular and molecular characteristics observed both within individual tumors and among tumors within the same patient or across different patients. This heterogeneity manifests at multiple levels, including genetic, epigenetic, transcriptional, phenotypic, and spatial domains, each holding significance in deciphering HCC biology, predicting treatment responses, and formulating personalized therapeutic interventions [ 9 ]. Genetic heterogeneity in HCC tumors is evident through various genetic alterations such as mutations, copy number variations, and chromosomal rearrangements. Intra-tumoral genetic heterogeneity arises from distinct genetic mutations in different regions within a single tumor, while inter-tumoral genetic heterogeneity manifests as unique genetic profiles across different tumors from the same patient or among different patients. Epigenetic heterogeneity, characterized by variations in DNA methylation, histone modifications, and chromatin remodeling, contributes to differences in gene expression patterns, cellular differentiation states, and responses to therapy within and between HCC tumors [ 10 ]. Transcriptional heterogeneity in HCC tumors is reflected in diverse gene expression profiles, indicative of variability in cellular phenotypes, functional states, and signaling pathway activities, potentially influenced by tumor cell populations, microenvironmental cues, and clonal evolution dynamics. Phenotypic heterogeneity within HCC tumors encompasses variations in cellular morphology, proliferation rates, and expression of cell surface or lineage-specific markers, potentially stemming from clonal evolution, interactions with the tumor microenvironment, or stochastic processes. Spatial heterogeneity is observed in HCC tumors with distinct cellular and molecular features observed in different tumor regions, such as the tumor center, invasive front, and tumor-stromal interface, impacting tumor growth patterns, metastatic potential, and responses to localized therapies. Despite posing challenges for HCC diagnosis, prognosis, and treatment, tumor heterogeneity offers avenues for more personalized and effective therapeutic strategies. Comprehensive characterization utilizing multi-omics approaches, single-cell analysis, and spatial profiling techniques is imperative for advancing our understanding of HCC heterogeneity and devising tailored therapeutic interventions for individual patients, potentially mitigating treatment resistance and disease recurrence [ 11 ]. Differentiation plasticity/transdifferentiation in Tumor Heterogeneity: "Differentiation plasticity" and "transdifferentiation" are mechanisms through which cancer cells can alter their differentiation state or lineage identity, thereby acquiring characteristics of different cell types. These processes significantly contribute to tumor heterogeneity, which encompasses a multitude of cellular and molecular features observed within and among tumors. Intra-tumoral heterogeneity, occurring within a single tumor, manifests as cancer cells exhibiting varying degrees of differentiation plasticity and transdifferentiation [ 12 ]. This results in the coexistence of distinct cellular phenotypes within the tumor, resembling different stages of differentiation or even different cell lineages. For instance, some cancer cells may retain characteristics of the original tissue of origin, such as hepatocytes in hepatocellular carcinoma, while others undergo transdifferentiation into cell types resembling mesenchymal cells or other lineages, adding to the diverse cellular composition within tumors. Inter-tumoral heterogeneity, observed across different tumors, arises from variability in differentiation plasticity and transdifferentiation, leading to differences in cellular phenotypes and lineage identities. Even tumors originating from the same tissue of origin may display diverse differentiation states and lineage characteristics due to individual disparities in genetic background, environmental exposures, and microenvironmental influences [ 13 ]. Clonal evolution further contributes to inter-tumoral heterogeneity, as subpopulations of cancer cells with distinct differentiation properties emerge and proliferate over time, amplifying tumor diversity. The presence of differentiation plasticity and transdifferentiation within tumors significantly impacts tumor behavior, aggressiveness, and response to therapy [ 14 ]. Cells with different differentiation states may exhibit varying proliferative capacities, metastatic potential, and resistance to treatment. For example, cancer cells undergoing epithelial-to-mesenchymal transition (EMT) via transdifferentiation may acquire invasive properties and resistance to conventional therapies, fueling tumor progression and metastasis. The resulting heterogeneity poses challenges for cancer diagnosis, prognosis, and treatment, as therapies targeting specific cellular phenotypes or lineage markers may prove less effective against heterogeneous tumors [ 15 , 16 ]. Investigating Hepatocyte-specific Genes/Signaling Pathways/TFs to trace HCC Heterogeneity : 1. HNF4A Expression in Other Cell-Types: HNF4A (Hepatocyte Nuclear Factor 4 Alpha) serves as an important transcription factor crucial for the development and functionality of hepatocytes, overseeing the expression of genes critical for liver development, metabolism, and homeostasis. Despite its primary association with hepatocyte biology, HNF4A also manifests expression and functional significance in diverse cell types and tissues [ 17 ]. In the realm of intestinal epithelial cells, HNF4A's presence regulates cell differentiation and function, vital for maintaining the intestinal epithelial barrier and modulating nutrient absorption and metabolism. Deficiency in HNF4A within the intestine may result in developmental anomalies and compromised barrier integrity, impacting overall gastrointestinal health. In pancreatic β-cells, HNF4A holds indispensable roles in both developmental progression and functional integrity, orchestrating the expression of genes critical for β-cell differentiation, insulin secretion, and glucose metabolism [ 18 , 19 ]. Mutations in HNF4A are implicated in maturity-onset diabetes of the young type 1 (MODY1), characterized by insulin secretion defects stemming from β-cell dysfunction. Furthermore, within renal tubular cells of the kidney, HNF4A governs the expression of genes essential for renal development, electrolyte transport, and fluid balance, essential for ensuring proper renal tubular epithelial cell differentiation and function [ 20 , 21 ]. Dysregulation of HNF4A is associated with renal cysts and renal dysfunction in clinical contexts. During embryonic development, HNF4A emerges as a critical player in the differentiation of intestinal and pancreatic progenitor cells, steering their trajectory towards mature hepatocytes, pancreatic β-cells, and intestinal epithelial cells. This regulatory function ensures proper organogenesis and functionality. Additionally, in adipocytes within adipose tissue, HNF4A's presence dictates adipocyte differentiation, lipid metabolism, and adipokine secretion, implicating its role in metabolic disorders and obesity when dysregulated [ 22 , 23 ]. Collectively, HNF4A's widespread expression and multidimensional roles across various cell types underscore its significance in orchestrating diverse physiological processes throughout the body, transcending its conventional association solely with hepatocytes [ 24 , 25 ]. Presence or Role in Other Tumors: The influence of HNF4A (Hepatocyte Nuclear Factor 4 Alpha) on tumor pathogenesis extends beyond its conventional role in normal tissue development, encompassing various tumors where its presence or functions are discernible. In colorectal cancer (CRC), HNF4A's involvement in the development and homeostasis of intestinal epithelial cells is important [ 26 ]. Dysregulation of HNF4A expression or function has been implicated in CRC carcinogenesis, where reduced expression of HNF4A in CRC tumors compared to normal colon tissue is observed. Functioning as a tumor suppressor, HNF4A regulates genes governing cell proliferation, apoptosis, and differentiation, with loss of its function associated with tumor progression and adverse prognosis in CRC patients. Similarly, in pancreatic cancer, HNF4A plays a role in pancreatic development and β-cell differentiation, with dysregulation implicated in tumorigenesis [ 27 ]. Acting as a tumor suppressor, HNF4A governs genes involved in cell cycle control, epithelial-mesenchymal transition (EMT), and glucose metabolism. Reduced HNF4A expression correlates with increased tumor aggressiveness and diminished patient survival. In renal cell carcinoma (RCC), HNF4A's expression in renal tubular cells underscores its role in renal development and function. Dysregulation of HNF4A expression in RCC is linked to tumor progression and metastasis, with its tumor-suppressive functions mediated through genes controlling cell proliferation, apoptosis, and renal differentiation. In endometrial cancer, HNF4A's expression in the endometrium and its regulatory role in endometrial development and differentiation are significant [ 28 ]. Dysregulation of HNF4A expression in endometrial cancer is associated with tumor aggressiveness and poor prognosis, with its tumor-suppressive actions modulating genes significant for cell cycle regulation, hormone signaling, and epithelial integrity. Similarly, in prostate cancer, HNF4A's expression in the prostate gland impacts prostate development and differentiation [ 29 ]. Dysregulation of HNF4A expression in prostate cancer contributes to tumor progression and metastasis, with its tumor-suppressive functions mediated through genes controlling cell proliferation, differentiation, and androgen receptor signaling. Overall, HNF4A's contextual roles in diverse tumors underscore its significance as either a tumor suppressor or promoter, contingent upon cellular context and specific molecular pathways involved. Insights into HNF4A's role in tumor biology hold potential for developing novel therapeutic strategies in cancer treatment [ 30 , 31 ]. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC: Dysregulated expression of HNF4A in hepatocellular carcinoma (HCC) contributes significantly to the emergence of transdifferentiation and heterogeneity features through diverse mechanisms, drawing upon its roles in other cell types and tumors [ 32 , 33 ]. Primarily, HNF4A serves as a key transcription factor in maintaining the identity and function of hepatocytes. Its dysregulated expression in HCC can precipitate the downregulation or loss of hepatocyte-specific genes, disrupting the genetic programming of hepatocytes and resulting in a loss of their characteristic identity. This loss of differentiation state sets a cellular context conducive to transdifferentiation into other cell types, thereby fostering intra-tumoral heterogeneity [ 34 ]. Moreover, dysregulated HNF4A expression may activate alternative differentiation pathways or lineage-specifying transcription factors within HCC cells. For instance, HNF4A's regulatory roles in various cell types such as intestinal epithelial cells, pancreatic β-cells, or renal tubular cells may be invoked, leading to the activation of alternative differentiation programs. Consequently, HCC cells may transdifferentiate into cell types resembling these diverse lineages, further fueling heterogeneity. Furthermore, HNF4A normally maintains the stability and lineage commitment of hepatocytes, suppressing their plasticity and preventing lineage switching. However, dysregulated expression in HCC disrupts this regulatory function, fostering enhanced cellular plasticity and increasing the propensity for transdifferentiation. HCC cells with dysregulated HNF4A expression exhibit greater flexibility in adopting alternative cell fates, thereby contributing to intra-tumoral heterogeneity. Additionally, dysregulated HNF4A expression may perturb signaling pathways crucial for cell fate determination and differentiation, such as Wnt/β-catenin, Notch, or TGF-β pathways. Such alterations, as observed in pancreatic cancer, can promote epithelial-to-mesenchymal transition (EMT) or induce stemness programs, thereby facilitating transdifferentiation and fostering tumor heterogeneity within HCC. HNF4A's interactions with other transcription factors and co-regulators are disrupted by its dysregulated expression in HCC. This disruption can lead to aberrant activation or repression of downstream target genes, further contributing to the emergence of transdifferentiation and heterogeneity features within the tumor [ 35 ]. Dysregulated expression of HNF4A in HCC disrupts hepatocyte identity, activates alternative differentiation pathways, enhances cellular plasticity, alters signaling pathways, and perturbs the interplay with other transcription factors. These mechanisms collectively contribute to the emergence of transdifferentiation and heterogeneity features within the tumor, underscoring the importance of understanding these processes in elucidating HCC pathogenesis and devising targeted therapeutic strategies [ 36 ]. 2. HNF1A Expression in Other Cell-Types: HNF1A (Hepatocyte Nuclear Factor 1 Alpha) is a transcription factor. It plays roles in hepatocyte development and function. However, its influence extends beyond hepatocytes, encompassing various other cell types and tissues [ 37 ]. In pancreatic β-cells, crucial for regulating blood glucose levels through insulin secretion, HNF1A orchestrates the expression of genes governing β-cell differentiation, insulin secretion, and glucose metabolism. Mutations in HNF1A are linked to maturity-onset diabetes of the young type 3 (MODY3), characterized by impaired insulin secretion owing to β-cell dysfunction. Similarly, HNF1A asserts its presence in intestinal epithelial cells, where it governs their differentiation and function, influencing nutrient absorption, epithelial barrier integrity, and mucosal immunity. Mutations in HNF1A have implications in intestinal disorders like inflammatory bowel disease (IBD) and colorectal cancer [ 38 ]. Moreover, in renal tubular cells, HNF1A regulates genes important for renal development, electrolyte transport, and fluid balance, with mutations associated with renal cysts and dysfunction. In endometrial epithelial cells of the uterus, HNF1A's regulatory role extends to endometrial development, differentiation, and menstrual cycle regulation. Its involvement in endometrial disorders such as hyperplasia and cancer underscores its significance in uterine health [ 39 , 40 , 41 ]. Additionally, in gastric epithelial cells, HNF1A governs genes essential for gastric development, mucin production, and acid secretion. Its implications in gastric disorders like gastritis, ulcers, and cancer highlight its role in gastric health. HNF1A demonstrates widespread expression and diverse roles across multiple cell types and tissues beyond hepatocytes [ 42 , 43 ]. Presence or Role in Other Tumors: The developmental influence of HNF1A (Hepatocyte Nuclear Factor 1 Alpha) transcends its conventional role, also shaping the pathogenesis of diverse tumors. In pancreatic cancer, HNF1A's involvement in pancreatic β-cell development and function is significant. Dysregulation of HNF1A expression or function is implicated in pancreatic cancer progression, where it acts as a tumor suppressor by governing genes critical for cell cycle control, differentiation, and glucose metabolism [ 44 , 45 ]. Reduced HNF1A expression correlates with increased tumor aggressiveness and diminished patient survival. Similarly, in colorectal cancer (CRC), HNF1A's presence in the intestinal epithelium influences cell differentiation and function. Dysregulation of HNF1A expression is observed in CRC, where it may serve as a tumor suppressor by modulating genes involved in cell proliferation, apoptosis, and epithelial barrier integrity. Loss of HNF1A function correlates with tumor progression and metastasis in CRC. Moreover, in renal cell carcinoma (RCC), HNF1A's expression in renal tubular cells plays a crucial role in renal development and function. Dysregulation of HNF1A expression in RCC is linked to tumor aggressiveness and poor prognosis, with its tumor-suppressive functions mediated through genes controlling cell cycle control, epithelial differentiation, and renal homeostasis. In endometrial cancer, HNF1A's regulatory role in the endometrial epithelium extends to endometrial development and differentiation [ 46 ]. Dysregulation of HNF1A expression contributes to tumor aggressiveness and poor prognosis in endometrial cancer, where it acts as a tumor suppressor by modulating genes involved in cell cycle regulation, hormone signaling, and epithelial integrity. Furthermore, in gastric cancer, HNF1A's expression in the gastric epithelium influences gastric development and function. Dysregulation of HNF1A expression in gastric cancer is associated with tumor progression and metastasis, with its tumor-suppressive actions modulating genes governing cell proliferation, differentiation, and gastric mucin production [ 47 , 48 ]. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC: Dysregulated expression of HNF1A in hepatocellular carcinoma (HCC) can contribute to the emergence of transdifferentiation and heterogeneity features through various mechanisms, considering its roles in other cell types and tumors. HNF1A plays a critical role in maintaining the identity and function of hepatocytes by regulating the expression of hepatocyte-specific genes [ 49 ]. Dysregulated expression of HNF1A in HCC may lead to the downregulation or loss of expression of hepatocyte-specific genes, disrupting the genetic programming of hepatocytes and causing a loss of hepatocyte identity. This loss of differentiation state may create a cellular context conducive to transdifferentiation into other cell types, contributing to heterogeneity within the tumor. Moreover, dysregulated HNF1A expression may activate alternative differentiation pathways or lineage-specifying transcription factors in HCC cells [ 50 ]. For instance, in pancreatic β-cells, HNF1A regulates genes involved in insulin secretion and glucose metabolism. Dysregulation of HNF1A in HCC may lead to the activation of these alternative differentiation programs, driving transdifferentiation of HCC cells into cell types resembling pancreatic β-cells, intestinal epithelial cells, or other cell types where HNF1A plays a role. Furthermore, HNF1A is involved in maintaining the stability and lineage commitment of hepatocytes, suppressing their plasticity and preventing lineage switching. Dysregulated expression of HNF1A in HCC may disrupt this regulatory function, leading to enhanced cellular plasticity and an increased propensity for transdifferentiation [ 51 ]. HCC cells with dysregulated HNF1A expression may exhibit greater flexibility in adopting alternative cell fates, such as acquiring features of pancreatic β-cells, intestinal epithelial cells, or other cell types where HNF1A is involved. Additionally, dysregulated HNF1A expression in HCC may affect signaling pathways involved in cell fate determination and differentiation. For instance, in colorectal cancer, HNF1A regulates genes involved in intestinal development and homeostasis. Dysregulation of HNF1A in HCC may lead to alterations in signaling pathways such as Wnt/β-catenin, Notch, or TGF-β, which promote epithelial-to-mesenchymal transition (EMT) or induce stemness programs, facilitating transdifferentiation and promoting heterogeneity within the tumor. Moreover, HNF1A interacts with other transcription factors and co-regulators to regulate gene expression networks involved in cell differentiation and function. Dysregulated expression of HNF1A in HCC may disrupt these interactions, leading to aberrant activation or repression of downstream target genes and contributing to the emergence of transdifferentiation and heterogeneity features [ 52 , 53 ]. 3. FOXA1/2 Expression in Other Cell-Types: FOXA1 and FOXA2 (Forkhead Box A1 and A2) are transcription factors with roles extending beyond hepatocytes, encompassing essential functions in various cell types [ 54 ]. In lung epithelial cells, FOXA1 and FOXA2 orchestrate lung development and maturation, regulating genes crucial for respiratory epithelial cell differentiation, surfactant production, and airway maintenance throughout lung development stages. In pancreatic β-cells, FOXA1 and FOXA2 contribute significantly to pancreatic development, particularly in insulin-producing β-cell differentiation and function. Their regulation of genes involved in pancreas organogenesis, glucose metabolism, and insulin secretion is integral, and disruptions in their expression can impede pancreatic development and disrupt glucose homeostasis. Similarly, in prostate epithelial cells, FOXA1 holds prominence, governing prostate gland morphogenesis, differentiation, and epithelial identity maintenance. Its regulatory role extends to genes pertinent to prostate-specific functions, such as prostate-specific antigen (PSA) expression, with dysregulation correlating with prostate cancer progression [ 55 ]. In breast epithelial cells, FOXA1 assumes significance, influencing mammary gland development, and differentiation. Its modulation of genes associated with mammary gland morphogenesis, milk production, and hormone responsiveness is important, with FOXA1 expression linked to luminal epithelial cell fate and hormone receptor-positive breast cancer subtypes [ 56 ]. Moreover, in endometrial epithelial cells, FOXA1 regulates genes important for endometrial development, differentiation, and response to hormonal cues. Its involvement in establishing endometrial receptivity for embryo implantation underscores its significance, while its implications in endometrial disorders, including endometrial cancer, highlight its multidimensional role. FOXA1 and FOXA2's broad expression and diverse functions across multiple cell types underscore their integral roles in coordinating various physiological processes throughout the body, beyond their conventional hepatocytic domain [ 57 , 58 ]. Presence or Role in Other Tumors: The developmental significance of FOXA1 and FOXA2 transcends their conventional roles in tissue development, as they exert influence over the pathogenesis of diverse tumors [ 59 ]. In prostate cancer, FOXA1 serves as a key transcription factor governing prostate development and differentiation. Dysregulated FOXA1 expression commonly characterizes prostate cancer, correlating with disease advancement and adverse prognosis. FOXA1 orchestrates genes integral to androgen receptor (AR) signaling, epithelial differentiation, and prostate-specific gene expression, thereby fostering tumor growth and survival [ 60 ]. Moreover, FOXA1's association with the luminal subtype of prostate cancer underscores its role in hormone receptor-positive tumors. Similarly, in breast cancer, FOXA1's expression in luminal epithelial cells imparts crucial contributions to mammary gland development and hormone responsiveness. Altered FOXA1 expression accompanies breast cancer progression, particularly evident in hormone receptor-positive subtypes. FOXA1 regulates genes implicated in estrogen receptor (ER) signaling, luminal epithelial differentiation, and mammary gland morphogenesis, positively correlating with favorable prognoses in ER-positive breast cancer patients [ 61 ]. In lung cancer, FOXA1 and FOXA2's involvement in lung development and their expression in lung epithelial cells tie them to tumorigenesis. Dysregulated expression potentially fuels lung cancer progression and metastasis by influencing epithelial differentiation and tumor cell plasticity, owing to their regulation of genes pertinent to lung maturation, surfactant production, and airway maintenance. In pancreatic cancer, FOXA1 and FOXA2's roles in pancreatic development and function position them as crucial players in tumorigenesis [ 62 ]. Dysregulated expression is associated with tumor aggressiveness and poor prognosis, impacting pancreas organogenesis, insulin secretion, and glucose metabolism. Perturbations in expression may alter pancreatic progenitor cell differentiation, tumor cell survival, and metastatic propensity. Moreover, in endometrial cancer, FOXA1's involvement in endometrial development and hormone responsiveness implicates its role in pathogenesis. Dysregulated expression influences endometrial receptivity, hormone signaling, and epithelial differentiation, potentially driving tumor progression by modulating proliferation, hormone receptor expression, and response to hormonal therapy. In essence, dysregulated FOXA1 and FOXA2 expression in various tumors disrupts tissue development and homeostasis, fostering tumor progression and metastasis. Elucidating their roles in tumor biology holds promise for devising novel therapeutic strategies in cancer treatment [ 63 , 64 ]. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC: Dysregulated expression of FOXA1 and FOXA2 in hepatocellular carcinoma (HCC) can fuel the emergence of transdifferentiation and heterogeneity features through various mechanisms, considering their roles in other cell types and tumors [ 65 ]. These mechanisms encompass loss of hepatocyte identity, activation of alternative differentiation pathways, enhanced cellular plasticity, altered signaling pathways, and interplay with other transcription factors. FOXA1 and FOXA2 play important roles in maintaining hepatocyte identity and function by regulating the expression of hepatocyte-specific genes. Dysregulated expression in HCC may lead to downregulation or loss of these genes, disrupting hepatocyte genetic programming and causing loss of hepatocyte identity. This loss of differentiation may foster a context conducive to transdifferentiation into other cell types, fostering intra-tumoral heterogeneity [ 66 ]. Moreover, dysregulated FOXA1/2 expression may activate alternative differentiation pathways or lineage-specifying transcription factors in HCC cells. For instance, in lung epithelial cells, FOXA1/2 regulate genes involved in lung development. Dysregulation in HCC might activate these pathways, driving transdifferentiation into cell types resembling lung epithelial cells or other types where FOXA1/2 are active. Furthermore, FOXA1 and FOXA2 normally maintain cell identity and stability, suppressing cellular plasticity. Dysregulated expression may disrupt this function, increasing cellular plasticity and the propensity for transdifferentiation. HCC cells with altered FOXA1/2 expression may exhibit greater flexibility in adopting alternative cell fates [ 67 , 68 , 69 ]. Altered FOXA1/2 expression in HCC may also affect signaling pathways involved in cell fate determination. For example, dysregulation could lead to changes in pathways like Wnt/β-catenin or Notch, promoting epithelial-to-mesenchymal transition or stemness programs, thus facilitating transdifferentiation and promoting heterogeneity [ 70 ]. FOXA1 and FOXA2 interact with other transcription factors to regulate gene expression networks. Dysregulated expression in HCC may disrupt these interactions, leading to aberrant activation or repression of downstream target genes, thereby contributing to the emergence of transdifferentiation and heterogeneity features within the tumor [ 71 , 72 , 73 ]. 4. CEBPA Expression in Other Cell-Types: CEBPA (CCAAT/enhancer-binding protein alpha) is a transcription factor recognized for its roles in the development and function of various cell types beyond hepatocytes. In myeloid cells, CEBPA holds a central position, governing their development and differentiation into granulocytes, monocytes, and dendritic cells. It orchestrates the expression of genes important for myeloid lineage commitment, maturation, and function, particularly promoting granulopoiesis and neutrophil differentiation [ 74 ]. Moreover, in adipocytes, CEBPA emerges as a critical regulator of adipogenesis, steering precursor cells towards maturation into mature adipocytes. It exercises control over genes implicated in adipocyte differentiation, lipid metabolism, and adipokine secretion, thereby facilitating the formation of white adipose tissue and preserving metabolic equilibrium. In lung epithelial cells, CEBPA contributes to lung development and differentiation in the maturation of alveolar epithelial cells. It oversees the expression of genes vital for lung morphogenesis, surfactant production, and gas exchange, with its deficiency potentially resulting in compromised alveolar development and respiratory impairments [ 75 ]. Similarly, in intestinal epithelial cells, CEBPA's involvement spans intestinal development, barrier function, and mucosal immunity. It plays a key role in steering intestinal stem cells towards differentiation into mature epithelial cell lineages like enterocytes and goblet cells. Dysregulation or deficiency of CEBPA in the intestine may disrupt epithelial homeostasis and escalate intestinal inflammation. Furthermore, in breast epithelial cells, CEBPA's influence is evident in mammary gland development and differentiation, particularly in the formation of luminal epithelial cells [ 76 ]. It governs the expression of genes crucial for mammary gland morphogenesis, milk production, and hormone responsiveness, positioning itself as a marker of luminal epithelial cell fate and hormone receptor-positive breast cancer subtypes [ 77 ]. Presence or Role in Other Tumors: The developmental biology of CEBPA (CCAAT/enhancer-binding protein alpha) extends beyond its role in normal tissue development, as it also influences the pathogenesis of various tumors. CEBPA's presence or roles can be traced in other tumors: CEBPA is frequently mutated in Acute Myeloid Leukemia (AML), occurring in approximately 10–15% of cases. Mutations can affect both the N-terminal transactivation domain and the C-terminal DNA-binding basic region, leading to loss of function or dominant-negative effects [ 78 ]. Some AML cases exhibit CEBPA double mutations, altering transcriptional regulation and promoting myeloid progenitor proliferation. In liver cancer, particularly hepatocellular carcinoma (HCC), CEBPA's role is significant. While mutations in CEBPA are less common in HCC compared to AML, dysregulated expression can occur through various mechanisms, impacting hepatocyte differentiation and promoting tumor progression [ 79 ]. CEBPA expression is associated with breast cancer progression and prognosis. Elevated expression in luminal-type tumors correlates with better outcomes, whereas downregulation in aggressive subtypes like triple-negative breast cancer contributes to tumor aggressiveness and therapy resistance. Dysregulation of CEBPA has been observed in lung cancer, particularly non-small cell lung carcinoma (NSCLC). Expression levels vary across NSCLC subtypes and disease stages, with increased expression linked to better prognosis in some cases and decreased expression associated with tumor progression and metastasis in others. In colorectal cancer (CRC), CEBPA expression levels fluctuate throughout tumor development stages, influencing cell proliferation, differentiation, and metastasis [ 80 , 81 ]. However, the specific roles of CEBPA in CRC biology are yet to be fully understood. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC: Dysregulated expression of CEBPA (CCAAT/enhancer-binding protein alpha) in hepatocellular carcinoma (HCC) can contribute to the emergence of transdifferentiation and heterogeneity features through various mechanisms, considering its roles in other cell types and tumors. CEBPA is crucial for maintaining hepatocyte identity and function by regulating the expression of hepatocyte-specific genes [ 82 , 83 ]. Dysregulated expression in HCC may disrupt the genetic programming of hepatocytes, leading to a loss of hepatocyte identity. Consequently, this loss of differentiation state may facilitate transdifferentiation into other cell types, contributing to tumor heterogeneity. Dysregulated CEBPA expression may activate alternative differentiation pathways or lineage-specifying transcription factors in HCC cells. For instance, in myeloid cells, CEBPA regulates genes involved in differentiation [ 84 ]. This dysregulation in HCC may drive transdifferentiation into myeloid-like cells or other cell types where CEBPA plays a role. CEBPA is involved in maintaining cell identity and stability, suppressing cellular plasticity, and preventing lineage switching. Dysregulated expression in HCC may disrupt this regulatory function, leading to enhanced cellular plasticity. Consequently, HCC cells with dysregulated CEBPA expression may exhibit greater flexibility in adopting alternative cell fates. Dysregulated CEBPA expression in HCC may affect signaling pathways involved in cell fate determination and differentiation [ 85 ]. Alterations in signaling pathways such as Wnt/β-catenin, Notch, or TGF-β may promote epithelial-to-mesenchymal transition (EMT) or induce stemness programs, facilitating transdifferentiation and promoting heterogeneity within the tumor. CEBPA interacts with other transcription factors and co-regulators to regulate gene expression networks involved in cell differentiation and function. Dysregulated expression in HCC may disrupt these interactions, leading to aberrant activation or repression of downstream target genes and contributing to the emergence of transdifferentiation and heterogeneity features [ 86 ]. 5. GATA4/6 Expression in Other Cell-Types: GATA4 and GATA6 are transcription factors renowned for their roles in various developmental processes beyond hepatocytes. Their presence or roles can be traced in the development of numerous other cell types. In cardiomyocytes, GATA4 and GATA6 are crucial for heart development and function, regulating genes involved in cardiac lineage specification, cardiomyocyte proliferation, and cardiac morphogenesis [ 87 ]. These transcription factors, expressed in cardiac progenitor cells, contribute to cardiogenesis and are associated with congenital heart defects and cardiomyopathies. Endodermal derivatives, such as the lungs, pancreas, and gastrointestinal tract, also rely on GATA4 and GATA6 for proper development. In the lung, these factors control genes necessary for lung branching morphogenesis, epithelial differentiation, and surfactant production. Similarly, in the pancreas, they oversee pancreatic progenitor cell fate and β-cell differentiation, while in the gastrointestinal tract, they regulate gut tube patterning, epithelial differentiation, and mucosal homeostasis [ 88 ]. GATA4 and GATA6 play essential roles in ovarian granulosa cells, where they govern folliculogenesis and steroidogenesis by orchestrating granulosa cell proliferation, differentiation, and response to gonadotropin stimulation. Dysregulated expression in these cells can disrupt ovarian follicle development, potentially leading to infertility or ovarian dysfunction. Moreover, GATA4 and GATA6 are involved in adrenal cortex development and steroid hormone biosynthesis. They regulate genes important for adrenocortical cell fate determination, steroidogenic enzyme expression, and adrenal gland morphogenesis [ 89 , 90 ]. Mutations in these transcription factors can result in adrenal insufficiency and congenital adrenal hyperplasia. In the testis, particularly in Sertoli cells, GATA4 plays a significant role in testicular development and spermatogenesis. It oversees genes responsible for Sertoli cell differentiation, germ cell support, and blood-testis barrier formation. Disruptions in GATA4 expression within Sertoli cells can impede testicular development and spermatogenesis, potentially leading to male infertility [ 91 , 92 ]. Presence or Role in Other Tumors: The developmental biology of GATA4 and GATA6 extends beyond normal tissue development, as these transcription factors are also implicated in the pathogenesis of various tumors. Here's how their presence or roles can be traced in other tumors. In cardiac tumors, particularly rare pediatric cardiac tumors like rhabdomyomas and teratomas, dysregulation of GATA4 and GATA6 has been observed [ 93 ]. These tumors often exhibit abnormal expression patterns of these transcription factors, potentially contributing to their pathogenesis. However, further research is required to fully understand their role in cardiac tumor development [ 94 , 95 ]. GATA4 and GATA6 are involved in gastric development and differentiation, and their dysregulation has been implicated in gastric cancer. Aberrant expression of these factors has been associated with gastric tumor progression, metastasis, and patient prognosis. They may modulate genes involved in gastric epithelial differentiation, proliferation, and invasion, thereby contributing to gastric cancer pathogenesis [ 96 ]. In pancreatic cancer, GATA6 is frequently dysregulated, playing diverse roles in tumor progression and metastasis. Its upregulation in pancreatic ductal adenocarcinoma (PDAC) correlates with poor patient outcomes. GATA6 regulates genes involved in pancreatic development, epithelial-to-mesenchymal transition (EMT), and metastasis, fostering tumor aggressiveness and metastatic spread in pancreatic cancer. Ovarian cancer, particularly endometrioid and clear cell ovarian carcinomas, also exhibits dysregulation of GATA4 and GATA6. Their aberrant expression is associated with tumor progression, chemoresistance, and patient survival. These transcription factors may influence genes involved in ovarian epithelial differentiation, hormone signaling, and tumor cell proliferation, thus contributing to ovarian cancer pathogenesis [ 97 ]. In colorectal cancer, dysregulation of GATA6 is observed, associated with tumor progression and metastasis. Elevated expression of GATA6 is detected in colorectal adenocarcinomas and correlates with poor patient prognosis. It regulates genes involved in intestinal epithelial differentiation, Wnt/β-catenin signaling, and epithelial-to-mesenchymal transition (EMT), thereby promoting colorectal cancer metastasis and invasion [ 98 ]. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC: GATA4 and GATA6 play essential roles in maintaining hepatocyte identity and function by regulating the expression of hepatocyte-specific genes. Dysregulated expression of these factors in HCC may lead to the downregulation or loss of expression of hepatocyte-specific genes, disrupting the genetic programming of hepatocytes and causing a loss of hepatocyte identity [ 99 ]. This loss of differentiation state may create a cellular context conducive to transdifferentiation into other cell types, contributing to heterogeneity within the tumor. Dysregulated GATA4/6 expression may activate alternative differentiation pathways or lineage-specifying transcription factors in HCC cells. For example, in cardiac tumors, GATA4 and GATA6 dysregulation has been observed, indicating their potential to influence cardiac differentiation programs [ 100 ]. Dysregulation of these factors in HCC may lead to the activation of these alternative differentiation programs, driving transdifferentiation of HCC cells into cardiac-like cells or other cell types where GATA4/6 play a role. GATA4 and GATA6 are involved in maintaining cell identity and stability, suppressing cellular plasticity, and preventing lineage switching. Dysregulated expression of these factors in HCC may disrupt this regulatory function, leading to enhanced cellular plasticity and increased propensity for transdifferentiation. HCC cells with dysregulated expression of GATA4/6 may exhibit greater flexibility in adopting alternative cell fates, such as acquiring features of cardiac cells, endodermal derivatives, or other cell types where GATA4/6 are involved [ 101 , 102 ]. Dysregulated GATA4/6 expression in HCC may affect signaling pathways involved in cell fate determination and differentiation. For example, in pancreatic cancer, GATA6 dysregulation influences pancreatic differentiation and tumor progression. Dysregulation of these factors in HCC may lead to alterations in signaling pathways such as Wnt/β-catenin, Notch, or TGF-β, which promote epithelial-to-mesenchymal transition (EMT) or induce stemness programs, facilitating transdifferentiation and promoting heterogeneity within the tumor. GATA4 and GATA6 interact with other transcription factors and co-regulators to regulate gene expression networks involved in cell differentiation and function. Dysregulated expression of these factors in HCC may disrupt these interactions, leading to aberrant activation or repression of downstream target genes and contributing to the emergence of transdifferentiation and heterogeneity features [ 103 , 104 ]. 6. PROX1 Expression in Other Cell-Types: PROX1 (Prospero homeobox protein 1) is a transcription factor with diverse roles in the development and function of various cell types beyond hepatocytes. Here's how its presence or roles can be traced in the development of other cell types. In lymphatic endothelial cells, PROX1 serves as a master regulator of lymphatic endothelial cell development and lymphangiogenesis [ 105 ]. It is expressed in lymphatic endothelial progenitors and controls the expression of genes involved in lymphatic vessel specification, differentiation, and maintenance. Throughout life, PROX1 remains essential for the formation of the lymphatic vasculature, ensuring the regulation of lymphatic endothelial cell identity. Expressed in neural progenitor cells, PROX1 contributes to neural development and neurogenesis. It governs genes associated with neural progenitor cell proliferation, differentiation, and migration. Particularly vital for the central nervous system, PROX1 aids in the development of regions such as the cerebral cortex, hippocampus, and cerebellum, facilitating the establishment of neuronal circuits and synaptic connections. Within lens epithelial cells, PROX1 plays a crucial role in lens development and differentiation. It oversees genes necessary for lens fiber cell differentiation, lens morphogenesis, and maintaining lens transparency. Ensuring the perpetuation of lens epithelial cell identity and lens homeostasis is among the fundamental tasks carried out by PROX1 throughout an organism's life [ 106 , 107 ]. In liver sinusoidal endothelial cells (LSECs), PROX1's expression is significant as it governs their development and function. By regulating genes involved in liver sinusoid formation, blood vessel integrity, and hepatic metabolism, PROX1 plays a vital role in maintaining the fenestrated phenotype of LSECs and promoting liver homeostasis. Within thyroid follicular cells, PROX1 participates in thyroid development and folliculogenesis. It regulates genes that contribute to thyroid follicle formation, thyroid hormone synthesis, and iodine metabolism. Essential for thyroid follicular cell differentiation and thyroid hormone production, PROX1's presence ensures proper functioning of the thyroid gland [ 108 , 109 , 110 ]. Presence or Role in Other Tumors: The developmental biology of PROX1 (Prospero homeobox protein 1) extends beyond normal tissue development, as PROX1 dysregulation is implicated in the pathogenesis of various tumors. PROX1 is a master regulator of lymphatic endothelial cell development and lymphangiogenesis [ 111 ]. Dysregulated PROX1 expression has been observed in lymphatic endothelial tumors such as lymphangiomas and lymphangiosarcomas. Aberrant expression of PROX1 may contribute to tumor angiogenesis, lymphatic vessel proliferation, and tumor metastasis by promoting lymphangiogenesis and lymphatic vessel invasion. PROX1 dysregulation has been implicated in hepatocellular carcinoma (HCC) [ 112 ]. While PROX1 is normally expressed in hepatocytes and liver sinusoidal endothelial cells (LSECs), its expression is often downregulated or lost in HCC. Reduced PROX1 expression in HCC is associated with tumor progression, metastasis, and poor patient prognosis. PROX1 acts as a tumor suppressor in HCC by inhibiting tumor cell proliferation, inducing apoptosis, and suppressing angiogenesis. PROX1 dysregulation has been reported in thyroid cancer, particularly in papillary thyroid carcinoma (PTC) and anaplastic thyroid carcinoma (ATC). PROX1 expression is upregulated in thyroid cancer cells compared to normal thyroid tissue, and its expression levels correlate with tumor aggressiveness and patient prognosis. PROX1 promotes thyroid cancer cell proliferation, migration, and invasion by regulating genes involved in epithelial-mesenchymal transition (EMT), angiogenesis, and metastasis [ 113 ]. PROX1 dysregulation has been associated with breast cancer progression and metastasis. In breast cancer, PROX1 expression is upregulated in invasive breast cancer subtypes compared to normal breast tissue, and its expression levels correlate with tumor grade, lymph node metastasis, and patient survival. PROX1 promotes breast cancer cell invasion and metastasis by regulating genes involved in EMT, extracellular matrix remodeling, and tumor cell dissemination. PROX1 dysregulation has been implicated in colon cancer progression and metastasis [ 114 , 115 ]. In colon cancer, PROX1 expression is upregulated in invasive tumor tissues compared to normal colon epithelium, and its expression levels correlate with tumor stage and patient prognosis. PROX1 promotes colon cancer cell invasion and metastasis by regulating genes involved in EMT, cell motility, and tumor-stroma interactions [ 116 , 117 , 118 ]. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC: PROX1 is normally expressed in hepatocytes and liver sinusoidal endothelial cells (LSECs) and plays a role in maintaining hepatocyte identity and function. Dysregulated expression of PROX1 in HCC may lead to the downregulation or loss of hepatocyte-specific genes, disrupting the genetic programming of hepatocytes and causing a loss of hepatocyte identity [ 119 ]. This loss of differentiation state may create a cellular context conducive to transdifferentiation into other cell types, contributing to heterogeneity within the tumor. Dysregulated PROX1 expression may activate alternative differentiation pathways or lineage-specifying transcription factors in HCC cells [ 120 ]. For example, PROX1 is a master regulator of lymphatic endothelial cell development and lymphangiogenesis. Dysregulation of PROX1 in HCC may lead to the activation of these alternative differentiation programs, driving transdifferentiation of HCC cells into lymphatic endothelial-like cells or other cell types where PROX1 plays a role. PROX1 is involved in maintaining cell identity and stability, suppressing cellular plasticity, and preventing lineage switching [ 121 ]. Dysregulated expression of PROX1 in HCC may disrupt this regulatory function, leading to enhanced cellular plasticity and increased propensity for transdifferentiation. HCC cells with dysregulated PROX1 expression may exhibit greater flexibility in adopting alternative cell fates, such as acquiring features of lymphatic endothelial cells, neural progenitor cells, or other cell types where PROX1 is involved. Dysregulated PROX1 expression in HCC may affect signaling pathways involved in cell fate determination and differentiation. For example, PROX1 dysregulation has been implicated in thyroid cancer progression, where it promotes tumor cell proliferation, migration, and invasion [ 122 ]. Dysregulation of PROX1 in HCC may lead to alterations in signaling pathways such as Wnt/β-catenin, Notch, or TGF-β, which promote epithelial-to-mesenchymal transition (EMT) or induce stemness programs, facilitating transdifferentiation and promoting heterogeneity within the tumor. PROX1 interacts with other transcription factors and co-regulators to regulate gene expression networks involved in cell differentiation and function. Dysregulated expression of PROX1 in HCC may disrupt these interactions, leading to aberrant activation or repression of downstream target genes and contributing to the emergence of transdifferentiation and heterogeneity features [ 123 , 124 ]. 7. SOX9 Expression in Other Cell-Types: SOX9 is a transcription factor with diverse roles in the development and differentiation of various cell types beyond hepatocytes. Its presence or roles can be traced in the development of several other cell types. SOX9 is a master regulator of chondrogenesis, expressed in chondroprogenitor cells, where it plays a critical role in their differentiation into chondrocytes [ 125 ]. Regulating the expression of genes essential for cartilage matrix synthesis, such as collagen type II and aggrecan, SOX9 is indispensable for cartilage development and skeletal morphogenesis. In the testis, SOX9 is expressed in Sertoli cells, contributing significantly to testicular development by regulating their differentiation and the formation of testicular cords. This transcription factor is crucial for male sex determination and the maintenance of testicular structure and function. In pancreatic development, SOX9 is involved in the differentiation of pancreatic progenitor cells into endocrine and exocrine cell lineages. It regulates genes crucial for pancreatic morphogenesis and is essential for the formation of pancreatic ducts and the differentiation of pancreatic progenitor cells into ductal epithelial cells [ 126 , 127 ]. SOX9 also plays a role in hair follicle development and regeneration, expressed in hair follicle stem cells and regulating genes involved in stem cell maintenance, hair follicle morphogenesis, and hair cycling. It is vital for maintaining hair follicle stem cell populations and regenerating hair follicles during the hair growth cycle. Moreover, SOX9 is expressed in colonic epithelial cells, contributing to colonic development and homeostasis by regulating genes involved in epithelial differentiation, barrier function, and mucosal immunity [ 128 , 129 ]. Essential for maintaining colonic epithelial integrity, SOX9 helps balance proliferation and differentiation of colonic epithelial cells [ 130 ]. Presence or Role in Other Tumors: SOX9 plays a significant role in various aspects of tumorigenesis and tumor progression across different types of cancers. Its involvement in other tumors can be observed as follows. In colorectal cancer (CRC), SOX9 is frequently upregulated and implicated in tumor initiation, progression, and metastasis [ 131 ]. It regulates genes associated with epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cells, and metastatic spread. Elevated SOX9 expression in CRC correlates with poor prognosis and resistance to chemotherapy. Moreover, in pancreatic ductal adenocarcinoma (PDAC), SOX9 is overexpressed and linked to tumor aggressiveness and unfavorable patient outcomes. It governs genes involved in cancer cell proliferation, invasion, and metastasis. The expression of SOX9 in PDAC is associated with tumor grade, lymph node metastasis, and patient survival, suggesting its potential as both a prognostic marker and therapeutic target [ 132 ]. In breast cancer, SOX9 expression correlates with disease progression and metastasis. It regulates genes implicated in cancer cell proliferation, migration, and invasion, and is involved in maintaining breast cancer stem cells. Elevated SOX9 levels in breast cancer are associated with poor prognosis and resistance to therapy. Similarly, SOX9 plays a critical role in prostate cancer initiation and progression by regulating genes involved in cancer cell proliferation, survival, and metastasis. Its expression is heightened in advanced prostate cancer, including castration-resistant prostate cancer (CRPC) and metastatic disease [ 133 , 134 ]. Targeting SOX9 in prostate cancer could be a promising therapeutic approach to inhibit tumor growth and metastasis. Additionally, SOX9 is upregulated in glioblastoma, a highly aggressive brain tumor, where it contributes to tumor invasiveness and poor patient prognosis [ 135 , 136 ]. It controls genes associated with glioblastoma cell migration, invasion, and angiogenesis. SOX9 expression in glioblastoma is linked to tumor recurrence and resistance to therapy, indicating its potential as a therapeutic target in this malignancy [ 137 , 138 ]. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC: SOX9, although not typically expressed in mature hepatocytes, can be upregulated in liver cancer, including hepatocellular carcinoma (HCC). This dysregulated expression of SOX9 may result in the downregulation or loss of hepatocyte-specific genes, disrupting the genetic programming essential for maintaining hepatocyte identity [ 139 , 140 ]. Consequently, this loss of differentiation state within HCC cells may create an environment conducive to transdifferentiation into alternative cell types, thereby contributing to the heterogeneity observed within the tumor. Moreover, dysregulated SOX9 expression in HCC may trigger the activation of alternative differentiation pathways or lineage-specifying transcription factors. For instance, SOX9 is important in chondrogenesis and the development of various cell types like chondrocytes. Hence, its dysregulation in HCC could potentially activate chondrogenic differentiation programs, prompting the transdifferentiation of HCC cells into chondrocyte-like cells or other cell types where SOX9 exerts influence [ 141 ]. SOX9's involvement in maintaining cellular plasticity and regulating cell fate decisions is well-documented. In the context of HCC, dysregulated expression of SOX9 may disrupt the normal cellular hierarchy and enhance cellular plasticity. This enhanced plasticity could enable HCC cells to adopt alternative cell fates, thereby facilitating their transdifferentiation into different cell types and contributing to the observed tumor heterogeneity. Furthermore, dysregulated SOX9 expression in HCC may impact various signaling pathways crucial for cell fate determination and differentiation. For example, SOX9 is implicated in the Wnt/β-catenin signaling pathway, which is frequently dysregulated in HCC [ 142 ]. Such dysregulation of SOX9 might lead to aberrant activation of Wnt/β-catenin signaling, thereby promoting epithelial-to-mesenchymal transition (EMT) and facilitating the transdifferentiation of HCC cells into mesenchymal-like cells or other cell types. Additionally, SOX9's interactions with other transcription factors and co-regulators play an important role in regulating gene expression networks involved in cell differentiation and function. Dysregulated expression of SOX9 in HCC could disrupt these interactions, resulting in aberrant activation or repression of downstream target genes. This disruption may contribute to the emergence of transdifferentiation and heterogeneity features observed within HCC tumors [ 143 , 144 ]. 8. Notch2 Expression in Other Cell-Types: NOTCH2, a signaling receptor, is involved in various cellular processes and developmental pathways across diverse tissues and organs. Its significance extends to the development of several cell types: In neural progenitor cells, NOTCH2 assumes a crucial role in neurogenesis and the establishment of the central nervous system. By orchestrating the delicate balance between neural stem cell self-renewal and differentiation, NOTCH2 governs the expression of genes important for neural fate specification [ 145 , 146 ]. Consequently, NOTCH2 signaling is indispensable for maintaining the pool of neural progenitor cells and driving neuronal differentiation during the process of brain development [ 147 , 148 ]. Furthermore, NOTCH2 signaling exerts profound effects on hematopoiesis and the differentiation of hematopoietic stem cells (HSCs) into diverse blood cell lineages. It regulates the balance between HSC self-renewal and differentiation into essential immune cell types such as T cells, B cells, and myeloid cells. By steering hematopoietic cell fate decisions, NOTCH2 signaling ensures the maintenance of immune cell homeostasis and effective immune responses [ 149 , 150 ]. Moreover, in intestinal epithelial cells, NOTCH2 signaling plays a key role in governing the development and equilibrium of the intestinal epithelium. By regulating intestinal stem cell dynamics along the crypt-villus axis, NOTCH2 activation facilitates the differentiation of intestinal progenitors into functional absorptive enterocytes and secretory goblet cells. This orchestrated process contributes significantly to intestinal epithelial renewal and barrier integrity. In the context of skeletal development and bone remodeling, NOTCH2 signaling assumes significance in the differentiation of osteoblast precursor cells into mature osteoblasts, responsible for bone formation and mineralization [ 151 ]. Additionally, NOTCH2 signaling influences the differentiation of osteoclast precursor cells into bone-resorbing osteoclasts, thereby contributing to the crucial balance of bone remodeling and homeostasis. In renal tubular epithelial cells, NOTCH2 signaling orchestrates kidney development and the maintenance of renal tubular epithelial cell function. By regulating the proliferation, differentiation, and polarization of renal tubular epithelial cells, NOTCH2 signaling contributes significantly to kidney morphogenesis and tubular integrity. However, dysregulated NOTCH2 signaling has been implicated in various kidney diseases, including polycystic kidney disease and renal fibrosis, underscoring its critical role in renal health and pathology [ 152 ]. Presence or Role in Other Tumors: NOTCH2, a key player in cellular processes and development, is also entangled in the web of tumorigenesis and cancer progression across diverse cancer types [ 153 , 154 ]. In colorectal cancer (CRC), NOTCH2 signaling emerges as a complex orchestrator, assuming a dual role as both a tumor suppressor and an oncogene. While it fosters cell differentiation and curtails proliferation, its aberrant activation can fuel CRC development by fostering tumor growth, invasion, and metastasis. Likewise, in breast cancer, NOTCH2 signaling influences disease progression and metastasis by governing crucial aspects of cancer cell behavior such as proliferation, survival, invasion, and stem cell properties [ 155 , 156 ]. Dysregulated NOTCH2 signaling heralds aggressive breast cancer subtypes, dismal prognosis, and therapy resistance, prompting exploration of NOTCH2 inhibitors as potential therapeutic modalities. Moreover, in hepatocellular carcinoma (HCC), NOTCH2 signaling assumes a central role in driving tumorigenesis and progression. Its dysregulation in HCC orchestrates a cascade of events, including enhanced tumor cell proliferation, survival, invasion, and metastasis, thereby fueling tumor aggressiveness and therapeutic resistance. In pancreatic cancer, NOTCH2 signaling emerges as a formidable force propelling tumor initiation and advancement [ 157 , 158 ]. Activation of NOTCH2 signaling fuels pancreatic cancer cell proliferation, survival, invasion, and metastasis, thereby contributing to poor patient prognosis and resistance to therapy, thereby underscoring its potential as a therapeutic target. In renal cell carcinoma (RCC), NOTCH2 signaling plays very important roles in disease evolution and progression. Dysregulated NOTCH2 expression in RCC cells drives tumor cell proliferation, angiogenesis, and metastasis, ultimately culminating in aggressive disease manifestations and adverse patient outcomes, highlighting its significance as a prognostic marker and therapeutic target in RCC management [ 159 , 160 ]. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC: NOTCH2 signaling, crucial for maintaining hepatocyte identity and function, may falter in HCC, disrupting the normal genetic programming of hepatocytes. This disruption could lead to the downregulation or loss of hepatocyte-specific genes, fostering a cellular milieu conducive to transdifferentiation into other cell types, thus fostering tumor heterogeneity [ 161 ]. Furthermore, dysregulated NOTCH2 expression in HCC may spur the activation of alternative differentiation pathways or lineage-specifying transcription factors. By invoking programs associated with intestinal epithelial cells or pancreatic progenitor cells, NOTCH2 dysregulation might drive transdifferentiation of HCC cells into phenotypes resembling these lineages. Moreover, NOTCH2 signaling's role in regulating cellular plasticity and fate determination is pertinent. Dysregulated NOTCH2 expression might disrupt the delicate balance between self-renewal and differentiation, heightening cellular plasticity within the HCC microenvironment and facilitating the adoption of alternative cell fates, thereby contributing to intratumoral heterogeneity [ 162 ]. Additionally, dysregulated NOTCH2 expression in HCC may perturb signaling pathways involved in cell fate determination and differentiation. Crosstalk between NOTCH2 signaling and pathways like Wnt/β-catenin and TGF-β could lead to aberrant pathway activation, further promoting transdifferentiation and augmenting tumor heterogeneity. Finally, the interplay of NOTCH2 with other transcription factors and co-regulators is important. Dysregulated NOTCH2 expression might disrupt these interactions, culminating in aberrant activation or repression of downstream target genes, thus contributing to the emergence of transdifferentiation and heterogeneity features within HCC tumors [ 163 , 164 ]. 9. HNF6 Expression in Other Cell-Types: HNF6 (Hepatocyte Nuclear Factor 6), also referred to as ONECUT1, stands as a significant transcription factor primarily acknowledged for its significant roles in hepatocyte development and functionality. Nevertheless, its influence extends beyond hepatocytes, encompassing crucial involvement in the development of various other cell types: In pancreatic development, HNF6 orchestrates the differentiation of both endocrine and exocrine cell lineages. It holds a critical sway over the development of beta cells, responsible for insulin secretion, alongside other endocrine cell variants like alpha and delta cells [ 165 , 166 ]. Additionally, HNF6 shapes the differentiation landscape of pancreatic exocrine cells, including acinar cells and ductal cells, thus contributing to the structural and functional integrity of the pancreas. Moreover, HNF6 emerges as a key player in the development and sustenance of biliary epithelial cells, which furnish the bile ducts and contribute to bile production and excretion. Its regulatory control over genes governing bile duct formation, bile acid metabolism, and epithelial cell differentiation within the liver and bile ducts underscores its indispensability in bile duct development and the onset of cholangiopathies [ 167 ]. Furthermore, HNF6's expression in intestinal epithelial cells is essential for intestinal development and maintenance. It assumes responsibility for regulating genes that govern intestinal epithelial cell differentiation, barrier function, and mucosal immunity, ensuring the structural integrity of the intestinal lining and maintaining the delicate balance between epithelial cell proliferation and differentiation. In neuronal populations, particularly within the central nervous system, HNF6's presence directs neuronal differentiation and functionality. Its involvement in crucial processes like neuronal migration, axon guidance, and synaptic connectivity during brain development underscores its significance. However, dysregulated expression of HNF6 has been implicated in various neurodevelopmental disorders and neurodegenerative diseases [ 168 ]. In adrenal gland development, HNF6 exercises regulatory control over the differentiation of adrenal cortex cells, particularly in the formation of steroidogenic cells. These cells, critical for the synthesis of hormones like cortisol and aldosterone, are crucial for adrenal gland morphogenesis and the initiation of steroid hormone production, thus highlighting the multidimensional role of HNF6 in adrenal gland development and functionality [ 169 ]. Presence or Role in Other Tumors: In pancreatic cancer, HNF6's involvement has been underscored, influencing the regulation of genes pertinent to pancreatic cell differentiation and function. Dysregulated expression of HNF6 within this context may foster tumor initiation, progression, and metastasis, a correlation that aligns with poorer prognosis and aggressive tumor behavior among affected patients [ 170 ]. Similarly, in colorectal cancer (CRC), HNF6's impact extends to the orchestration of intestinal epithelial cell dynamics. Perturbations in HNF6 expression levels have been noted, potentially influencing tumor development and progression. The expression levels of HNF6 correlate with critical parameters like tumor grade, metastatic potential, and patient survival, hinting at its promise as both a prognostic marker and a therapeutic target in CRC [ 171 ]. Furthermore, in prostate cancer, HNF6 emerges as a significant player in disease trajectory, modulating genes crucial for prostate epithelial cell differentiation and function. Dysregulated HNF6 expression has been implicated in heightened cancer aggressiveness and metastatic potential, aligning with observations of its association with tumor stage, recurrence rates, and patient outcomes. In breast cancer, HNF6's presence in tumor tissues suggests its potential involvement in disease progression. Dysregulated expression of HNF6 correlates with indicators of aggressive tumor behavior, metastatic propensity, and patient prognosis. Its association with tumor grade, hormone receptor status, and patient survival underscores its relevance as a prognostic marker and therapeutic target in breast cancer management [ 172 ]. In neuroendocrine tumors, HNF6's regulatory influence over neuroendocrine cell differentiation and function signifies its role in tumor development and progression within this context. Dysregulated HNF6 expression levels are implicated in tumor aggressiveness and hormone secretion, aligning with observations of its correlation with tumor grade, hormone secretion levels, and patient outcomes. This highlights its potential utility as a prognostic marker and therapeutic target in neuroendocrine tumors [ 173 , 174 ]. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC : The dysregulated expression of HNF6 in HCC can disturb the genetic blueprint essential for hepatocyte integrity, possibly leading to the attenuation or loss of hepatocyte-specific genes. Consequently, this deviation from the hepatocyte differentiation state could foster an environment conducive to transdifferentiation, thus fostering tumor heterogeneity [ 175 ]. Furthermore, the aberrant expression of HNF6 may not only perturb the conventional differentiation pathways but also activate alternative programs or lineage-specifying factors within HCC cells. Drawing parallels with its role in pancreatic differentiation, dysregulation of HNF6 might propel HCC cells towards acquiring pancreatic-like phenotypes, thereby further enhancing tumor heterogeneity. Moreover, HNF6's involvement extends to the regulation of cellular plasticity and fate determination. In the context of HCC, dysregulated HNF6 expression could disrupt the delicate equilibrium between self-renewal and differentiation, thereby augmenting cellular plasticity. This augmented plasticity may empower HCC cells to adopt diverse cellular identities, thereby contributing to intratumoral heterogeneity [ 176 ]. Additionally, dysregulated HNF6 expression in HCC could disrupt signaling pathways important for cell fate determination and differentiation. HNF6 crosstalks with pathways like Wnt/β-catenin and TGF-β, its dysregulation might trigger aberrant pathway activation, fostering transdifferentiation events and fueling tumor heterogeneity. Finally, HNF6's interactions with various transcription factors and co-regulators play a crucial role in governing gene expression networks crucial for cell fate decisions. In the context of HCC, dysregulated HNF6 expression could perturb these interactions, resulting in aberrant downstream gene regulation. This dysregulation may culminate in the emergence of transdifferentiation events and contribute significantly to the heterogeneity observed within HCC tumors [ 177 , 178 ]. 10. ONECUT2/ HNF6β Expression in Other Cell-Types : ONECUT2, also known as HNF6β, extends its influence beyond hepatocytes, manifesting crucial roles in various cell types during development. In pancreatic progenitor cells, ONECUT2 orchestrates pancreatic development by steering the differentiation of both endocrine and exocrine cell lineages. It fosters the emergence of vital endocrine cell types like insulin-producing beta cells, glucagon-producing alpha cells, and somatostatin-producing delta cells [ 179 ]. Additionally, ONECUT2 contributes to the formation of pancreatic exocrine cells such as acinar and ductal cells, essential for digestive enzyme secretion and pancreatic fluid homeostasis. Within the central nervous system, ONECUT2 exerts its influence during neuronal development. By guiding neuronal differentiation and axonal growth, it facilitates the establishment of neuronal circuits and synaptic connections. These actions contribute to the development of diverse neuronal subtypes crucial for sensory and motor functions, including motor neurons, interneurons, and sensory neurons [ 180 ]. In intestinal epithelial cells, ONECUT2 regulates intestinal development and maintenance. It steers the differentiation of intestinal stem cells into specialized epithelial cell types like absorptive enterocytes and secretory goblet cells. Moreover, ONECUT2 bolsters intestinal barrier function and mucosal immunity, safeguarding against microbial intrusion and preserving intestinal equilibrium. Within the adrenal cortex, ONECUT2 participates in adrenal gland development by overseeing the differentiation of steroidogenic cells. These cells, nestled in distinct zones like the zona glomerulosa and zona fasciculata, synthesize essential steroid hormones like cortisol and aldosterone, thereby contributing to systemic homeostasis. Finally, in renal tubular epithelial cells, ONECUT2 plays a crucial role in kidney development [ 181 ]. By regulating the differentiation of nephron progenitor cells into various renal tubular epithelial cell types, it ensures the formation of proximal tubule cells, distal tubule cells, and collecting duct cells. Furthermore, ONECUT2 upholds renal tubular integrity and function, essential for maintaining electrolyte balance and fluid homeostasis [ 182 ]. Presence or Role in Other Tumors : ONECUT2, also termed HNF6β, emerges as a significant player in the context of tumorigenesis and tumor progression across a spectrum of cancer types. In pancreatic cancer, ONECUT2 exhibits elevated expression levels, thereby fostering tumor growth, invasion, and metastasis by orchestrating the activation of genes governing proliferation, survival, and epithelial-mesenchymal transition (EMT). The heightened ONECUT2 expression correlates with dismal prognostic outcomes and reduced survival rates among pancreatic cancer patients [ 183 ]. Similarly, in colorectal cancer, ONECUT2 is overexpressed, exerting its influence on tumor cell behavior by fueling proliferation, migration, and invasion through the regulation of key genes involved in cell cycle control, apoptosis resistance, and EMT. Elevated ONECUT2 levels align with advanced tumor stage, lymph node metastasis, and inferior prognosis in colorectal cancer patients [ 184 ]. Prostate cancer presents another arena where ONECUT2 expression escalates, fostering tumor cell proliferation, survival, and androgen receptor (AR) signaling, thereby steering disease progression. Its regulatory influence extends to genes important for hormone response, cell cycle regulation, and metastasis, correlating with aggressive tumor phenotypes, biochemical recurrence, and castration-resistant prostate cancer (CRPC). In breast cancer, ONECUT2 emerges as an upregulated entity, perpetuating tumor cell proliferation, invasion, and metastasis by orchestrating gene networks governing cell cycle progression, angiogenesis, and tumor microenvironment remodeling [ 185 ]. Its heightened expression is associated with adverse prognostic indicators, metastatic dissemination, and resistance to therapy among breast cancer cohorts. In neuroendocrine tumors, ONECUT2 assumes an augmented expression profile, where it modulates genes instrumental in neuroendocrine cell differentiation and function. This phenomenon culminates in heightened tumor cell proliferation, hormone secretion, and metastatic propensity, aligning with advanced tumor stage, hormone hypersecretion, and compromised patient outcomes [ 186 ]. ONECUT2 emerges as a significant contributor to tumorigenesis and tumor progression across diverse cancer types, exerting its influence through gene regulatory networks that dictate crucial aspects of cancer cell behavior and disease trajectory [ 187 ]. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC : ONECUT2/HNF6β, a critical regulator of hepatocyte development and function, holds sway over the genetic programming essential for maintaining the identity of hepatocytes. In the context of HCC, aberrant expression of ONECUT2/HNF6β may perturb this delicate balance, resulting in the downregulation or loss of hepatocyte-specific genes, thereby paving the way for a cellular milieu conducive to transdifferentiation into alternative cell types, thereby fostering heterogeneity within the tumor [ 188 ]. Moreover, dysregulated expression of ONECUT2/HNF6β in HCC cells could instigate the activation of alternative differentiation pathways or lineage-specifying transcription factors, drawing parallels from its involvement in pancreatic cell differentiation and function. This aberration may propel the transdifferentiation of HCC cells towards acquiring a pancreatic-like phenotype, thereby augmenting the spectrum of cellular diversity within the tumor microenvironment. Furthermore, ONECUT2/HNF6β's involvement in regulating cellular plasticity and fate determination unveils another layer of complexity. Dysregulation of its expression in HCC may disrupt the equilibrium between self-renewal and differentiation, fostering an environment conducive to enhanced cellular plasticity [ 189 ]. This phenomenon could empower HCC cells with the ability to adopt alternative cell fates, thereby fueling the inherent heterogeneity observed within the tumor. Additionally, dysregulated expression of ONECUT2/HNF6β in HCC holds the potential to impinge upon signaling pathways crucial for cell fate determination and differentiation [ 190 ]. Through crosstalk with pathways such as Wnt/β-catenin and TGF-β, dysregulation of ONECUT2/HNF6β may trigger aberrant activation of these pathways, thereby orchestrating transdifferentiation processes and contributing to the heterogeneous landscape within the tumor microenvironment. Moreover, the interplay of ONECUT2/HNF6β with other transcription factors and co-regulators underscores its role in orchestrating gene expression networks important for cell differentiation and function. Dysregulated expression of ONECUT2/HNF6β in HCC may perturb these interactions, culminating in aberrant activation or repression of downstream target genes, thus potentiating the emergence of transdifferentiation and heterogeneity features within the tumor microenvironment [ 191 , 192 ]. 11. TBX3/18 Expression in Other Cell-Types : TBX3 and TBX18, members of the T-box transcription factor family, exert important roles in embryonic development, extending beyond hepatocytes to various other cell types. In cardiac cells, TBX3 and TBX18 are instrumental in shaping the architecture of the heart [ 193 ]. TBX3 contributes to the specification of pacemaker cells within the sinoatrial node, thus regulating heart rhythm, while TBX18 plays a crucial role in the differentiation and sustenance of cardiomyocytes, essential for cardiac function and the formation of the cardiac conduction system. These transcription factors also exert influence over the musculoskeletal system, participating in the development and differentiation of skeletal muscle, bone, and cartilage. TBX3 influences muscle development and regeneration, as well as skeletal patterning during limb formation, whereas TBX18 is vital for skeletal muscle and bone development, along with the specification of cartilage progenitor cells during embryogenesis [ 194 ]. Furthermore, TBX3 and TBX18 contribute significantly to the formation of urogenital structures, including the kidneys, bladder, and reproductive organs. TBX3 aids in the formation of the ureteric bud and branching morphogenesis of the kidney, as well as the development of the bladder and urethra, whereas TBX18 is involved in the differentiation of smooth muscle cells in the urinary tract and reproductive organs. In neural crest-derived cells, TBX3 and TBX18 play crucial roles in the development of craniofacial structures, peripheral neurons, and melanocytes [ 195 ]. TBX3 is integral to the patterning of craniofacial tissues and the specification of neural crest-derived cell lineages, while TBX18 contributes to the development of sensory neurons, glial cells in the peripheral nervous system, and the migration and differentiation of melanocytes. Moreover, TBX3 and TBX18 are implicated in the development of lymphatic vessels and lymphatic endothelial cells, crucial for immune function and tissue fluid homeostasis. TBX3 governs the specification and maintenance of lymphatic endothelial cell identity, as well as lymphangiogenesis, while TBX18 participates in the differentiation of lymphatic endothelial cells from venous endothelial precursors, thereby contributing to the formation of the lymphatic vasculature [ 196 ]. Presence or Role in Other Tumors : TBX3 and TBX18, both important in embryonic development as transcription factors, extend their influence to tumorigenesis and tumor progression across various cancer types. In breast cancer, TBX3's overexpression is linked to tumor advancement and metastasis, as it governs genes involved in cell proliferation, epithelial-to-mesenchymal transition (EMT), and metastasis, thereby influencing patient prognosis [ 197 ]. Similarly, TBX3 plays a significant role in melanoma progression and metastasis, regulating genes crucial for cell proliferation, invasion, and migration. Its heightened expression in melanoma tumors, particularly in metastatic lesions, correlates with advanced tumor stage and poor patient prognosis. In bladder cancer, elevated TBX3 expression levels are associated with tumor aggressiveness and adverse clinical outcomes, as it modulates genes governing cell proliferation, invasion, and metastasis, highlighting its significance in disease progression [ 198 ]. Dysregulation of TBX3 expression in lung cancer, especially non-small cell lung cancer (NSCLC), underscores its role in tumor proliferation, invasion, and metastasis, with its expression levels being indicative of tumor grade, lymph node involvement, and patient survival. Conversely, TBX18's involvement in prostate cancer is important, where its altered expression correlates with tumor aggressiveness, recurrence, and poor patient outcomes, as it regulates genes pertinent to cell proliferation, invasion, and metastasis. Moreover, in colorectal cancer (CRC), dysregulated expression levels of both TBX3 and TBX18 contribute to tumor progression and metastasis, influencing genes related to cell proliferation, invasion, and metastasis, thereby affecting patient survival and disease outcome [ 199 ]. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC : TBX3 and TBX18 are crucial in maintaining hepatocyte identity during development, essential for the normal genetic programing of hepatocytes. Dysregulated expression of TBX3/18 in hepatocellular carcinoma (HCC) may disrupt this programing, potentially leading to the downregulation or loss of hepatocyte-specific genes. Consequently, this loss of differentiation state could foster a cellular environment conducive to transdifferentiation into other cell types, thereby augmenting heterogeneity within the tumor [ 200 ]. Furthermore, dysregulated TBX3/18 expression in HCC cells might activate alternative differentiation pathways or lineage-specifying transcription factors. For instance, TBX3's involvement in cardiac and musculoskeletal cell development, along with TBX18's role in cardiac and urogenital cell development, suggests their potential to induce alternative differentiation programs in HCC cells. This could lead to the transdifferentiation of HCC cells into cell types characteristic of other tissues. Moreover, TBX3 and TBX18 are implicated in regulating cellular plasticity and fate determination across various cell types. Their dysregulated expression in HCC could disrupt the balance between self-renewal and differentiation, resulting in enhanced cellular plasticity [ 201 ]. Consequently, HCC cells may acquire the ability to adopt alternative cell fates, contributing further to tumor heterogeneity. Additionally, dysregulated TBX3/18 expression in HCC may influence signaling pathways crucial for cell fate determination and differentiation. Their interaction with signaling pathways such as Wnt/β-catenin, which is implicated in HCC pathogenesis, suggests a potential role in promoting transdifferentiation and heterogeneity within the tumor microenvironment. Furthermore, the interplay between TBX3/18 and other transcription factors and co-regulators is critical for regulating gene expression networks involved in cell differentiation and function [ 202 , 203 ]. 12. Wnt/β-catenin pathway Expression in Other Cell-Types : The Wnt/β-catenin signaling pathway stands as a regulator of development and homeostasis across various cell types, extending beyond hepatocytes. In embryonic stem cells (ESCs), this pathway assumes a crucial role in maintaining pluripotency and self-renewal [ 204 ]. Activation of Wnt signaling fosters ESC proliferation while preventing differentiation, thus preserving the undifferentiated state. Within the developing nervous system, the Wnt/β-catenin pathway governs the proliferation, differentiation, and migration of neural progenitor cells (NPCs). Activation of Wnt signaling expands neural progenitor cell populations and orchestrates the specification of neuronal and glial lineages [ 205 ]. For osteoblasts and chondrocytes, the Wnt/β-catenin pathway plays critical roles in skeletal development and bone homeostasis. It governs the proliferation and differentiation of osteoblast progenitors, promoting bone formation, and regulates chondrocyte differentiation, crucial for cartilage development and endochondral ossification. In the intestinal epithelium, the Wnt/β-catenin pathway is indispensable for development and maintenance [ 206 ]. It oversees the proliferation and differentiation of intestinal stem cells within the crypts, fostering epithelial cell renewal and tissue regeneration. Dysregulation of Wnt signaling in intestinal epithelial cells is associated with intestinal disorders and colorectal cancer. Regarding hair follicle stem cells, the Wnt/β-catenin pathway regulates their activation, proliferation, and differentiation in the skin. Activation of Wnt signaling supports hair follicle regeneration and hair growth, while its inhibition precipitates hair follicle degeneration and alopecia. In the realm of immune cells, the Wnt/β-catenin pathway plays a multifactorial role in development and function. It oversees immune cell differentiation, activation, and effector functions across T cells, B cells, and dendritic cells, thereby contributing to both innate and adaptive immune responses [ 207 ]. Presence or Role in Other Tumors : The Wnt/β-catenin signaling pathway emerges as a frequent target of dysregulation in various tumors, significantly contributing to tumorigenesis, tumor progression, and metastasis. In colorectal cancer (CRC), dysregulation of the Wnt/β-catenin pathway stands as a hallmark, characterized by mutations in APC, CTNNB1 (encoding β-catenin), or other pathway components. These mutations lead to aberrant activation of Wnt signaling, fostering tumor initiation and progression [ 208 ]. Activation of Wnt signaling fuels the proliferation, survival, and invasion of CRC cells, correlating with poor prognosis. Similarly, in hepatocellular carcinoma (HCC), frequent activation of the Wnt/β-catenin pathway contributes significantly to hepatocarcinogenesis. Mutations in CTNNB1 or AXIN1, resulting in β-catenin stabilization and nuclear translocation, are prevalent in HCC. This activation promotes HCC cell proliferation, survival, and metastasis, correlating with tumor aggressiveness and unfavorable patient outcomes. Dysregulated Wnt/β-catenin signaling is also implicated in various subtypes of breast cancer, where its activation promotes cell proliferation, survival, and metastasis [ 209 ]. The crosstalk between Wnt signaling and hormone receptor pathways, such as the estrogen receptor and HER2, contributes to endocrine therapy resistance and tumor recurrence. In lung cancer, particularly non-small cell lung cancer (NSCLC), aberrant activation of the Wnt/β-catenin pathway is frequently observed. Mutations in Wnt pathway components or alterations in Wnt ligand expression disrupt Wnt signaling regulation, fostering NSCLC cell proliferation, invasion, and resistance to therapy, correlating with advanced tumor stage and poor patient outcomes. Moreover, dysregulated Wnt/β-catenin signaling plays a significant role in pancreatic cancer progression. Mutations in Wnt pathway components or alterations in Wnt ligand expression drive aberrant activation of Wnt signaling in pancreatic cancer cells, promoting proliferation, invasion, and metastasis, and correlating with tumor aggressiveness and poor patient prognosis [ 210 ]. In melanoma, the Wnt/β-catenin pathway is also dysregulated, contributing to disease progression and metastasis. Activation of Wnt signaling promotes melanoma cell proliferation, survival, and invasion, correlating with tumor aggressiveness and unfavorable patient outcomes [ 211 ]. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC : The Wnt/β-catenin pathway stands out as an important regulator in maintaining hepatocyte identity and function. However, in hepatocellular carcinoma (HCC), dysregulated activation of this pathway can lead to the downregulation of hepatocyte-specific genes, resulting in the loss of hepatocyte identity. Consequently, this loss of differentiation state may create an environment conducive to transdifferentiation into other cell types, thereby contributing to the tumor's heterogeneity [ 212 ]. Furthermore, dysregulated Wnt/β-catenin signaling in HCC cells can activate alternative differentiation pathways or lineage-specifying transcription factors. For instance, it has been associated with the upregulation of genes involved in epithelial-mesenchymal transition (EMT) and stemness, potentially driving transdifferentiation into mesenchymal-like or progenitor-like cell states, thus adding to the tumor's heterogeneity. Moreover, the Wnt/β-catenin pathway's role in regulating cellular plasticity and fate determination is critical. Dysregulated expression of this pathway in HCC may enhance cellular plasticity, enabling cells to adopt alternative fates. This plasticity fosters the emergence of heterogeneous cell populations within the tumor, including those with stem-like properties, further contributing to its complexity [ 213 ]. Additionally, dysregulated Wnt/β-catenin signaling can influence the tumor microenvironment, altering interactions between cancer cells and stromal cells. Such alterations may promote the emergence of heterogeneous cell populations within the tumor and facilitate the transdifferentiation of HCC cells into cell types characteristic of other tissues, thereby amplifying heterogeneity [ 214 ]. Furthermore, the interplay between the Wnt/β-catenin pathway and other signaling pathways implicated in cell fate determination and differentiation is significant. Dysregulated crosstalk between Wnt/β-catenin signaling and pathways such as Notch, Hedgehog, or TGF-β pathways in HCC may exacerbate the emergence of transdifferentiation and heterogeneity features, further complicating the tumor landscape [ 215 , 216 , 217 ]. 13. FGF Expression in Other Cell-Types : Fibroblast Growth Factors (FGFs) play roles in the development and maintenance of various cell types. In neural cells, FGFs are indispensable for the formation and sustenance of the nervous system, influencing processes such as proliferation, differentiation, and survival of neural progenitor cells, as well as guiding axonal growth and synaptic plasticity, thereby contributing significantly to neurogenesis and gliogenesis [ 218 ]. Mesenchymal cells also rely on FGFs for their development and differentiation into different lineages like osteoblasts, chondrocytes, and adipocytes. FGFs orchestrate processes such as bone formation, cartilage development, and adipogenesis, crucial during skeletal development and tissue repair. Moreover, FGFs partake in wound healing, angiogenesis, and fibrosis, essential for tissue integrity and repair across various organs [ 219 ]. Epithelial tissues, including those in the skin, lungs, and gastrointestinal tract, depend on FGFs for their development, maintenance, and repair. FGFs regulate epithelial cell behavior, governing proliferation, differentiation, migration, and tissue morphogenesis, contributing significantly to organogenesis and tissue homeostasis. Vascular endothelial cells rely on FGFs for angiogenesis and vascular development [ 220 ]. These growth factors modulate endothelial cell functions such as proliferation, migration, tube formation, and blood vessel remodeling, critical for both embryonic vasculogenesis and postnatal vascular maintenance and repair. In muscle cells, FGFs play crucial roles in development and regeneration, particularly in skeletal and cardiac muscle. They regulate processes like myoblast proliferation, differentiation, and fusion, which are vital for muscle growth, repair, and function throughout life. Finally, FGFs exert influence on the development and function of various immune cell types [ 221 ]. They regulate immune cell proliferation, differentiation, and activation, as well as cytokine production and inflammatory responses. FGFs contribute to immune cell development in primary lymphoid organs and modulate immune cell trafficking and function in peripheral tissues, thereby playing crucial roles in immune system homeostasis and responses [ 222 ]. Presence or Role in Other Tumors : Fibroblast Growth Factors (FGFs) and their signaling pathways have significant implications in tumorigenesis, tumor progression, and metastasis across various types of cancers. In breast cancer, FGF signaling is frequently dysregulated, with overexpression of FGF ligands and receptors like FGF1, FGF2, and FGFR1 associated with tumor growth, angiogenesis, and metastasis [ 223 ]. This signaling cascade promotes breast cancer cell proliferation, survival, invasion, and resistance to therapy, ultimately correlating with poor prognosis. Similarly, dysregulated FGF signaling is evident in lung cancer, particularly in non-small cell lung cancer (NSCLC), where alterations in FGF ligands such as FGF2 and FGFRs contribute to tumorigenesis and progression. FGF signaling in NSCLC fosters cell proliferation, angiogenesis, and metastasis, linking to advanced tumor stage and unfavorable patient outcomes. In colorectal cancer (CRC), FGF signaling plays a crucial role in tumor development and progression, with upregulation of FGF ligands like FGF18 and FGFR4 observed in CRC tumors [ 224 ]. This signaling axis promotes CRC cell proliferation, survival, angiogenesis, and invasion, fueling tumor growth and metastasis. Prostate cancer pathogenesis involves dysregulated FGF signaling, characterized by the overexpression of FGF ligands such as FGF8 and FGFR1. This dysregulation contributes to tumor growth, angiogenesis, and progression to castration-resistant prostate cancer (CRPC). FGF signaling drives prostate cancer cell proliferation, survival, and invasion, presenting a potential therapeutic target in CRPC. Pancreatic cancer also exhibits dysregulated FGF signaling, with overexpression of FGF ligands such as FGF2 and FGF19, along with FGFRs, observed in pancreatic tumors [ 225 ]. This aberrant signaling promotes pancreatic cancer cell proliferation, survival, angiogenesis, and metastasis, aligning with poor patient outcomes. In melanoma, dysregulated FGF signaling contributes to tumor progression and therapy resistance, with alterations in FGF ligands like FGF2 and FGFRs detected in melanoma tumors. This signaling pathway promotes melanoma cell proliferation, survival, angiogenesis, and invasion, correlating with tumor aggressiveness and unfavorable prognosis [ 226 ]. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC : FGF signaling pathways exhibit the capability to induce alternative differentiation programs in HCC cells, potentially leading to the transdifferentiation of these cells into mesenchymal-like or stem-like states. This induction of alternative pathways can contribute significantly to the heterogeneity within the tumor by generating cell populations with distinct phenotypic and functional characteristics [ 227 ]. Moreover, dysregulated FGF expression in HCC can enhance cellular plasticity, allowing tumor cells to adopt alternative cell fates in response to microenvironmental cues or signaling inputs. This heightened plasticity often results in the emergence of diverse cell populations within the tumor, including those exhibiting stem-like properties or alternative lineage markers. Furthermore, FGF signaling can influence the tumor microenvironment by modulating interactions between cancer cells and stromal cells. In HCC, dysregulated FGF expression may alter the composition and function of the tumor microenvironment, fostering the emergence of heterogeneity [ 228 ]. For instance, FGF signaling can stimulate processes like angiogenesis, fibrosis, and immune cell recruitment, creating supportive niches for distinct subpopulations of HCC cells. Additionally, FGF signaling has been implicated in the activation of epithelial-mesenchymal transition (EMT), a process associated with increased cellular plasticity and invasive behavior in cancer cells. Dysregulated FGF expression in HCC may induce EMT in certain tumor cells, leading to the acquisition of mesenchymal features and further contributing to tumor heterogeneity, progression, metastasis, and resistance to therapy [ 229 ]. Moreover, FGF signaling pathways interplay with other signaling pathways involved in cell fate determination and differentiation. Perturbations in FGF expression in HCC can disrupt the balance of these pathways, leading to the emergence of transdifferentiation and heterogeneity features. For example, interactions between FGF and Wnt/β-catenin signaling pathways have been documented in HCC, highlighting their implications for tumor cell plasticity and heterogeneity [ 230 , 231 ]. 14. HGF Expression in Other Cell-Types : Hepatocyte Growth Factor (HGF), also known as scatter factor, exhibits various roles in the development and maintenance of multiple cell types beyond hepatocytes. HGF serves as mitogen for epithelial cells, regulating branching morphogenesis and tubulogenesis in tissues like the lung, kidney, and mammary gland during development [ 232 ]. It fosters the proliferation, survival, and migration of epithelial cells, thus contributing significantly to tissue morphogenesis and organ development. Moreover, HGF functions as a key regulator of angiogenesis and vascular development, stimulating endothelial cell proliferation, migration, and tube formation. This activity promotes the formation of new blood vessels during both embryonic development and tissue repair processes, ensuring proper vascularization of developing organs and maintaining vascular homeostasis in adult tissues [ 233 ]. In addition, HGF acts as a paracrine factor for mesenchymal cells such as fibroblasts and smooth muscle cells, regulating their proliferation, migration, and differentiation. This influence extends to tissue remodeling, wound healing, and organ fibrosis, where HGF signaling plays key roles in orchestrating mesenchymal-epithelial interactions during organ development and regeneration. Furthermore, HGF and its receptor, c-Met, are expressed in the nervous system, where they contribute to neurogenesis, neuronal migration, and synaptogenesis [ 234 ]. HGF supports the proliferation and survival of neural progenitor cells and facilitates neurite outgrowth and branching, thus influencing the development and plasticity of neuronal circuits in the brain and spinal cord. Additionally, HGF signaling is implicated in myogenesis and muscle regeneration, promoting the proliferation and differentiation of myoblasts and facilitating muscle fiber formation and repair. It also regulates myoblast migration and fusion during embryonic development and in response to muscle injury, ensuring proper muscle growth and regeneration. HGF influences the function of various immune cell types, including macrophages, T cells, and dendritic cells, by regulating their migration, cytokine production, and tissue infiltration [ 235 ]. This modulation of inflammatory responses and tissue repair processes contributes to immune cell recruitment to sites of injury or inflammation, ultimately aiding in tissue remodeling and regeneration. Overall, HGF plays diverse and crucial roles in the development and maintenance of multiple cell types, including epithelial, endothelial, mesenchymal, neural, muscle, and immune cells. Its signaling pathways are indispensable for tissue morphogenesis, organogenesis, and repair processes throughout the body [ 236 ]. Presence or Role in Other Tumors : Hepatocyte Growth Factor (HGF) and its receptor c-Met play significant roles in tumorigenesis, tumor progression, and metastasis across various types of cancers. In gastric cancer, dysregulated HGF/c-Met signaling is linked to disease progression and unfavorable prognosis. Gastric tumors often exhibit overexpression of HGF and c-Met, promoting tumor cell proliferation, invasion, and metastasis. Moreover, this signaling pathway contributes to angiogenesis and confers resistance to chemotherapy in gastric cancer cases. Similarly, in breast cancer, HGF/c-Met signaling is associated with metastasis and resistance to therapy. Elevated levels of HGF and c-Met are correlated with aggressive cancer phenotypes and adverse patient outcomes [ 237 ]. This signaling axis facilitates breast cancer cell migration, invasion, and metastasis to distant sites such as the lung and bone, while also fostering resistance to targeted therapies like HER2 inhibitors and endocrine therapy. In non-small cell lung cancer (NSCLC), dysregulated HGF/c-Met signaling is particularly important in cases of acquired resistance to EGFR inhibitors. Overexpression of HGF and c-Met correlates with tumor progression, metastasis, and poor prognosis among NSCLC patients. The pathway promotes NSCLC cell proliferation, survival, invasion, and resistance to targeted therapies, including EGFR inhibitors and immune checkpoint inhibitors [ 238 ]. Moreover, HGF/c-Met signaling is implicated in colorectal cancer (CRC) progression and metastasis. Elevated levels of HGF and c-Met are associated with advanced tumor stage, lymph node metastasis, and unfavorable prognosis in CRC patients. This signaling axis drives CRC cell proliferation, invasion, and metastasis to distant organs like the liver, contributing to resistance against chemotherapy and targeted therapies. Similarly, dysregulated HGF/c-Met signaling is observed in pancreatic cancer, promoting tumor progression, invasion, and metastasis. Overexpression of HGF and c-Met is linked to aggressive cancer phenotypes and poor patient outcomes in pancreatic cancer cases. The pathway facilitates pancreatic cancer cell proliferation, survival, angiogenesis, and metastasis to the liver and peritoneum, while also conferring resistance to chemotherapy and targeted therapies [ 239 ]. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC : Hepatocyte Growth Factor (HGF) plays a crucial role in promoting tumor heterogeneity and progression in Hepatocellular Carcinoma (HCC) through various mechanisms. HGF acts as an inducer of Epithelial-Mesenchymal Transition (EMT), prompting epithelial cells to lose their distinctive features and adopt mesenchymal traits. In HCC, dysregulated HGF expression triggers EMT in hepatocytes, resulting in the loss of hepatocyte-specific characteristics and the acquisition of mesenchymal properties [ 240 ]. This transition enhances cellular plasticity, fostering the emergence of diverse cell populations within the tumor. Moreover, HGF signaling pathways can activate alternative differentiation programs in HCC cells. By stimulating the expression of lineage-specific transcription factors and signaling molecules, HGF drives the transdifferentiation of hepatocytes into other cell types, such as progenitor-like cells or mesenchymal cells. This transdifferentiation process contributes to tumor heterogeneity and may fuel tumor progression and resistance to therapy. Additionally, HGF enhances cellular plasticity by promoting stemness and dedifferentiation in HCC cells [ 241 ]. Dysregulated HGF expression increases the stem-like properties of tumor cells, enabling them to adopt multiple cell fates and contribute to tumor heterogeneity. This enhanced cellular plasticity facilitates the emergence of therapy-resistant cell populations within the tumor. Furthermore, HGF can modulate the tumor microenvironment by stimulating the recruitment and activation of stromal cells, such as fibroblasts and immune cells [ 242 ]. Dysregulated HGF expression alters the composition and function of the tumor microenvironment, creating niches that support the survival and proliferation of heterogeneous cell populations. This microenvironmental modulation sustains tumor heterogeneity and promotes tumor progression. HGF signaling pathways crosstalk with other signaling pathways involved in cell fate determination and differentiation [ 243 , 244 ]. 15. TGF-β Expression in Other Cell-Types : Transforming Growth Factor-beta (TGF-β) is a multifunctional molecule involved in the development and maintenance of various cell types throughout the body. TGF-β serves as a crucial regulator of epithelial cell behavior, controlling differentiation, proliferation, and homeostasis [ 245 ]. It orchestrates epithelial-mesenchymal interactions during development, facilitating the formation of organs like the lung, skin, and mammary gland. By promoting epithelial cell differentiation while inhibiting proliferation, TGF-β contributes significantly to tissue morphogenesis and organ development. In mesenchymal cells, TGF-β signaling is vital for differentiation, migration, and matrix deposition. It guides the differentiation of mesenchymal stem cells into specialized cell types such as osteoblasts, chondrocytes, and adipocytes, essential for skeletal development and tissue repair. Moreover, TGF-β stimulates fibroblast activation and collagen production, key processes in tissue remodeling, wound healing, and fibrotic conditions. TGF-β signaling is indispensable for vascular development and angiogenesis, crucial for the formation of new blood vessels during embryogenesis and tissue repair [ 246 ]. It regulates endothelial cell behaviors like proliferation, migration, and tube formation, facilitating vascular growth and maturation. Additionally, TGF-β modulates interactions between endothelial cells and pericytes, as well as the deposition of basement membrane components, promoting vascular stability. In the immune system, TGF-β plays critical roles in cell differentiation, activation, and function. It regulates the differentiation of T cells, B cells, and macrophages, along with cytokine production and immune responses. Acting as an immune suppressor, TGF-β dampens inflammation and fosters immune tolerance in peripheral tissues [ 247 ]. Dysregulated TGF-β signaling is associated with conditions like autoimmune diseases and cancer immunosuppression. TGF-β signaling is also involved in neurogenesis, neuronal migration, and synaptogenesis within the developing nervous system. It guides the proliferation and differentiation of neural progenitor cells while influencing neurite outgrowth and branching. Additionally, TGF-β modulates synaptic plasticity and neurotransmitter release, contributing to the formation and function of neural circuits [ 248 ]. Presence or Role in Other Tumors : Transforming Growth Factor-beta (TGF-β) signaling plays a key role in tumorigenesis and tumor progression across various cancer types. In breast cancer, TGF-β signaling exhibits a dual role, functioning as a tumor suppressor in early stages but promoting tumor progression in advanced stages. Initially, TGF-β inhibits epithelial cell proliferation and induces apoptosis, exerting tumor-suppressive effects [ 249 ]. However, as breast cancer advances, cells often develop resistance to TGF-β's growth-inhibitory actions and exploit its pro-metastatic functions. This leads to the promotion of epithelial-mesenchymal transition (EMT), invasion, and metastasis, contributing to tumor aggressiveness. Similarly, in colorectal cancer (CRC), dysregulated TGF-β signaling is a hallmark of disease progression. Initially, TGF-β acts as a tumor suppressor by inhibiting epithelial cell proliferation and promoting apoptosis. However, during CRC progression, mutations often disrupt TGF-β signaling, abolishing its tumor-suppressive effects and activating pro-metastatic pathways [ 250 ]. Consequently, TGF-β promotes EMT, invasion, and metastasis, exacerbating tumor aggressiveness. In pancreatic cancer, dysregulated TGF-β signaling is frequently observed and associated with disease progression and metastasis. TGF-β promotes EMT, invasion, and metastasis in pancreatic tumors, while also stimulating the desmoplastic reaction and creating a tumor-promoting microenvironment. This dysregulation contributes to poor patient prognosis and therapeutic resistance [ 251 ]. Similarly, in lung cancer, TGF-β signaling exhibits complex roles. Initially acting as a tumor suppressor by inhibiting epithelial cell proliferation and inducing apoptosis, it later contributes to tumor aggressiveness as cancer cells acquire mutations that disrupt TGF-β signaling. This results in the promotion of EMT, invasion, and metastasis, ultimately leading to poor patient outcomes. In prostate cancer, dysregulated TGF-β signaling is implicated in disease progression and metastasis. TGF-β promotes EMT, invasion, and metastasis in prostate cancer cells, while also modulating the tumor microenvironment to support angiogenesis, immune evasion, and therapy resistance. This dysregulation contributes to tumor aggressiveness and metastatic spread in prostate cancer patients [ 252 ]. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC : Dysregulated expression of Transforming Growth Factor-beta (TGF-β) in hepatocellular carcinoma (HCC) can lead to the emergence of transdifferentiation and heterogeneity features through various mechanisms, considering its roles in other cell types and tumors [ 253 ]. TGF-β signaling serves as an inducer of epithelial-mesenchymal transition (EMT), prompting epithelial cells in HCC to lose their differentiated phenotype and acquire mesenchymal characteristics. This dysregulation triggers the loss of hepatocyte-specific features and the acquisition of mesenchymal traits, thereby increasing cellular plasticity and contributing to the emergence of heterogeneous cell populations within the tumor. Moreover, TGF-β signaling pathways can activate alternative differentiation programs in HCC cells by stimulating the expression of lineage-specific transcription factors and signaling molecules. This process drives the transdifferentiation of hepatocytes into other cell types, such as progenitor-like cells or mesenchymal cells, thereby generating cellular heterogeneity within the tumor and potentially fueling tumor progression and therapeutic resistance [ 254 ]. Additionally, TGF-β is recognized for its ability to enhance cellular plasticity by promoting stemness and dedifferentiation across various cell types. In HCC, dysregulated expression of TGF-β may augment the stem-like properties of tumor cells, enabling them to adopt multiple cell fates and contribute to tumor heterogeneity. Consequently, TGF-β-induced cellular plasticity may facilitate the emergence of therapy-resistant cell populations within the tumor microenvironment. Furthermore, TGF-β can modulate the tumor microenvironment by influencing the behavior of stromal cells, including fibroblasts, endothelial cells, and immune cells. This dysregulation alters the composition and function of the tumor microenvironment, creating niches that support the survival and proliferation of heterogeneous cell populations, thus contributing to the maintenance of tumor heterogeneity and promoting tumor progression [ 255 ]. Finally, TGF-β signaling pathways interact with other signaling pathways implicated in cell fate determination and differentiation, such as Wnt/β-catenin and Notch pathways. Dysregulated expression of TGF-β in HCC disrupts the balance of signaling pathways involved in maintaining hepatocyte identity and homeostasis, leading to the emergence of transdifferentiation and heterogeneity features. These interactions further exacerbate cellular plasticity and heterogeneity in HCC, contributing to tumor aggressiveness and progression [ 256 , 257 , 258 ]. 16. Hippo signaling pathway Expression in Other Cell-Types : Hippo signaling pathway, originally recognized for its involvement in regulating organ size and tissue growth, is fundamental for the development and maintenance of various cell types beyond hepatocytes. In epithelial cells, the Hippo pathway governs processes such as proliferation, differentiation, and polarity [ 259 ]. Across different tissues like the skin, intestine, and lung, Hippo signaling orchestrates epithelial morphogenesis and ensures barrier function. Activation of the Hippo pathway represses genes associated with cell proliferation while promoting the establishment of apical-basal polarity, critical for the proper formation and sustenance of epithelial tissues. Furthermore, Hippo signaling exerts influence on mesenchymal cells, including fibroblasts, smooth muscle cells, and osteoblasts [ 260 , 261 ]. During skeletal development, components of the Hippo pathway regulate the differentiation of mesenchymal stem cells into osteoblasts and chondrocytes, thereby contributing significantly to bone formation and remodeling. Additionally, Hippo signaling governs the contractility and migration of mesenchymal cells during tissue repair and organogenesis. In neural cells, Hippo signaling oversees neurogenesis, neuronal differentiation, and axon guidance within the developing nervous system. Particularly in the brain, components of the Hippo pathway control the proliferation and differentiation of neural progenitor cells, influencing cortical development and the formation of neuronal circuits [ 262 ]. Moreover, Hippo signaling modulates synaptic plasticity and dendritic arborization, both critical for proper neural circuit function. The Hippo pathway also participates in vascular development and angiogenesis, particularly concerning endothelial cells. By regulating endothelial cell proliferation, migration, and tube formation, Hippo signaling contributes to the genesis of new blood vessels during embryogenesis and tissue repair. However, dysregulated Hippo signaling can disrupt vascular morphogenesis and contribute to pathological angiogenesis, as seen in conditions like cancer and retinopathy [ 263 ]. Furthermore, Hippo signaling impacts the functionality of various immune cell types, encompassing T cells, B cells, and macrophages. Within the immune system, components of the Hippo pathway govern processes such as cell proliferation, differentiation, and cytokine production, thereby modulating immune responses and inflammation. Dysregulation of Hippo signaling has been associated with autoimmune diseases, cancer immunosuppression, and inflammatory disorders, highlighting its importance in immune regulation [ 264 ]. Presence or Role in Other Tumors : The Hippo signaling pathway, renowned for its role in regulating organ size and tissue growth during development, is also deeply involved in various tumors. In liver cancer (Hepatocellular carcinoma - HCC), dysregulated Hippo signaling is a common occurrence. This pathway, crucial for liver organ size and function, undergoes disruption in HCC, leading to aberrant activation of YAP (Yes-associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif), downstream effectors [ 265 ]. Consequently, YAP/TAZ activation fosters hepatocyte proliferation, stemness, and resistance to apoptosis, thereby fueling HCC development and progression. Similarly, dysregulated Hippo signaling surfaces in breast cancer, contributing to its progression and metastasis. Abnormal YAP and TAZ activation in breast cancer cells promote cell proliferation, survival, epithelial-mesenchymal transition (EMT), and metastasis, correlating with aggressive phenotypes and poor patient outcomes. Moreover, Hippo signaling dysregulation in breast cancer leads to therapy resistance, underscoring its potential as a therapeutic target. Colorectal cancer (CRC) also exhibits dysregulated Hippo signaling, impacting tumor initiation and advancement. The activation of YAP and TAZ promotes CRC cell proliferation, invasion, and metastasis, correlating with adverse clinicopathological characteristics and poor prognosis [ 266 ]. Furthermore, Hippo signaling modulation of the tumor microenvironment in CRC fosters angiogenesis, immune evasion, and therapy resistance. Likewise, in lung cancer, dysregulated Hippo signaling drives progression and metastasis. Aberrant YAP and TAZ activation in lung cancer cells fuel proliferation, EMT, invasion, and distant metastasis, aligning with aggressive tumor behavior and unfavorable patient outcomes. Moreover, dysregulated Hippo signaling contributes to therapy resistance in lung cancer, emphasizing its importance as a therapeutic target. In pancreatic cancer, dysregulated Hippo signaling promotes tumor progression and metastasis. Abnormal YAP and TAZ activation enhances pancreatic cancer cell proliferation, invasion, and metastasis to distant sites, correlating with poor prognosis and therapeutic resistance. Additionally, dysregulated Hippo signaling in pancreatic cancer shapes the tumor microenvironment, fostering desmoplasia and immune evasion [ 267 ]. Dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC : Hippo pathway, crucial for regulating cell proliferation and apoptosis, is disrupted in HCC, leading to uncontrolled cell growth and tumor heterogeneity. This dysregulation results in varying levels of proliferation among different cells within the tumor, contributing to its heterogeneous nature. Furthermore, activation of the Hippo pathway, particularly through the downregulation of its effectors YAP and TAZ, inhibits stemness properties in hepatic stem cells. However, dysregulated Hippo signaling in HCC may induce stem-like characteristics in tumor cells, fostering a heterogeneous cell population with varying degrees of differentiation. Moreover, dysregulated Hippo signaling, leading to the activation of YAP and TAZ, is associated with the induction of EMT in cancer cells [ 268 ]. This process involves epithelial cells losing their characteristics and acquiring mesenchymal traits, resulting in increased migratory and invasive properties and further contributing to tumor heterogeneity. Additionally, dysregulated Hippo signaling influences cell fate decisions and plasticity within HCC tumors. In response to changes in the tumor microenvironment or therapeutic pressures, HCC cells with altered Hippo signaling may undergo phenotypic switching between hepatocyte-like and progenitor-like states, adding to the observed heterogeneity. Furthermore, the Hippo pathway not only affects tumor cell behavior but also shapes the tumor microenvironment [ 269 ]. Dysregulated Hippo signaling alters the crosstalk between tumor cells and stromal, immune, and vascular cells, leading to changes in the tumor microenvironment that contribute to tumor heterogeneity. Finally, the heterogeneity driven by dysregulated Hippo signaling can confer resistance to therapies. Subpopulations of cells with different Hippo pathway activity may respond differently to treatment, allowing for the survival and proliferation of resistant clones, further complicating therapeutic interventions [ 270 ]. Discussion Emergence of HCC Heterogeneity and Transdifferentiation Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy characterized by diverse cellular phenotypes and molecular subtypes. Understanding the mechanisms driving HCC heterogeneity and transdifferentiation is crucial for developing effective therapeutic strategies and improving patient outcomes. In this discussion, we focus on key factors and pathways implicated in the emergence of HCC heterogeneity and transdifferentiation, including HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/Onecut1, ONECUT2/HNF6β, TBX3/18, Wnt/β-catenin pathway, FGF, HGF, TGF-β, and Hippo signaling pathway. Hepatocyte-Specific Transcription Factors HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, and SOX9 are critical regulators of hepatocyte differentiation and function. Dysregulation of these transcription factors disrupts the genetic programing of hepatocytes, leading to the emergence of heterogeneous cell populations within HCC tumors. For instance, downregulation of HNF4A and HNF1A has been associated with loss of hepatocyte identity and acquisition of progenitor-like traits in HCC cells. Similarly, aberrant expression of FOXA1/2, CEBPA, GATA4/6, PROX1, and SOX9 contributes to phenotypic diversity and transdifferentiation events in HCC. Signaling Pathways Activation of NOTCH, Wnt/β-catenin, FGF, HGF, TGF-β, and Hippo signaling pathways plays key roles in HCC heterogeneity and transdifferentiation. NOTCH signaling promotes cellular plasticity and self-renewal capacity in HCC cells, contributing to the maintenance of tumor heterogeneity. Dysregulated Wnt/β-catenin signaling induces EMT and promotes the emergence of cancer stem cells with enhanced tumorigenic potential. FGF and HGF signaling pathways stimulate hepatocyte proliferation and survival, driving the expansion of heterogeneous cell populations within HCC tumors. TGF-β signaling induces EMT and promotes the acquisition of mesenchymal characteristics in HCC cells. Dysregulated Hippo signaling disrupts cell-cell interactions and promotes YAP/TAZ-mediated transdifferentiation events in HCC. Interplay of Factors and Pathways The interplay between hepatocyte-specific transcription factors and signaling pathways contributes to the complex landscape of HCC heterogeneity and transdifferentiation. Crosstalk between these factors and pathways modulates cellular plasticity, differentiation state, and therapeutic response in HCC. For example, Hippo signaling regulates the expression of HNF4A and HNF6, thereby influencing hepatocyte differentiation and transdifferentiation events in HCC. Similarly, NOTCH signaling interacts with Wnt/β-catenin and TGF-β pathways to promote EMT and cancer stemness in HCC cells. Clinical Implications The heterogeneity and transdifferentiation observed in HCC have profound clinical implications for patient management and treatment outcomes. Understanding the molecular mechanisms driving these processes is essential for identifying novel therapeutic targets and developing precision medicine approaches tailored to individual patients. Targeting key transcription factors and signaling pathways involved in HCC heterogeneity and transdifferentiation holds promise for improving therapeutic efficacy and overcoming drug resistance in HCC. Future Directions The emergence of HCC heterogeneity and transdifferentiation is governed by a complex interplay of hepatocyte-specific transcription factors and signaling pathways. Elucidating the molecular mechanisms underlying these processes is essential for advancing our understanding of HCC pathogenesis and developing effective therapeutic strategies. Future research efforts should focus on uncovering the dynamic regulatory networks driving HCC heterogeneity and transdifferentiation, with the ultimate goal of improving patient outcomes in this deadly disease. Key Findings : Dysregulation of hepatocyte-specific genes and signaling pathways contributes to the emergence of heterogeneity and transdifferentiation in hepatocellular carcinoma (HCC). Key transcription factors such as HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, HNF6/Onecut1, and ONECUT2/HNF6β are dysregulated in HCC, disrupting hepatocyte genetic programming. Signaling pathways including the Wnt/β-catenin pathway, fibroblast growth factor (FGF) signaling, hepatocyte growth factor (HGF) signaling, transforming growth factor-beta (TGF-β) signaling, and the Hippo signaling pathway are dysregulated in HCC, influencing cellular fate decisions and promoting stemness. Dysregulation of NOTCH signaling components and TBX3/18 transcription factors further complicates the heterogeneity observed in HCC tumors. Investigating the dysregulated expression of hepatocyte-specific genes, transcription factors, and signaling pathways provides insights for targeted therapeutic interventions aimed at disrupting these pathways and improving patient outcomes in HCC. Conclusions The decline in the gene expression of hepatocyte cell type-specific genes dysregulates the genetic programming of hepatocytes involved in cell type-specific homeostasis. This fundamental disruption sets the stage for the emergence of heterogeneity within hepatocellular carcinoma (HCC). Through our investigation into the expression patterns of hepatocyte genes, transcription factors (TFs), and signaling pathways across different cell types and tumors, we have gained critical insights into the underlying mechanisms driving this heterogeneity and transdifferentiation in HCC. The dysregulation of hepatocyte-specific genes such as HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, and others serves as a cornerstone for the cellular plasticity observed in HCC. These genes, which play roles in hepatocyte development and homeostasis, are essential for maintaining cellular identity and function. However, their aberrant expression in HCC disrupts the delicate balance of hepatocyte-specific gene expression patterns, leading to The emergence of heterogeneous cell populations within the tumor. the dysregulated expression of key signaling pathways, including the Wnt/β-catenin pathway, FGF signaling, HGF signaling, TGF-β signaling, and the Hippo signaling pathway, further contributes to the phenotypic diversity and therapeutic resistance observed in HCC. Activation or inhibition of these pathways influences cellular behavior and modulates the tumor microenvironment, creating a complex landscape of heterogeneous cell populations with distinct molecular profiles and functional characteristics. The dysregulation of hepatocyte-specific genes and signaling pathways serves as a catalyst for the emergence of heterogeneity and transdifferentiation in HCC. The implications of our investigation extend beyond a mere understanding of HCC heterogeneity. By elucidating the molecular mechanisms driving cellular plasticity and transdifferentiation in HCC, we have laid the groundwork for the development of targeted therapeutic strategies aimed at disrupting these pathways and improving patient outcomes. Targeted inhibition of key transcription factors or signaling pathways implicated in HCC heterogeneity holds promise for overcoming therapeutic resistance and improving the efficacy of existing treatment modalities. Moreover, our findings underscore the importance of personalized medicine approaches in HCC management. The heterogeneity observed in HCC tumors necessitates tailored therapeutic interventions that account for the diverse molecular profiles and cellular phenotypes within individual tumors. By deciphering the molecular underpinnings of HCC heterogeneity, we can identify novel biomarkers for patient stratification and develop precision medicine strategies that target specific molecular vulnerabilities in HCC tumors. Abbreviations HCC: Hepatocellular carcinoma TFs: Transcription factors FGF: Fibroblast growth factor HGF: Hepatocyte growth factor TGF-β: Transforming growth factor-beta Wnt: Wingless-related integration site NOTCH: Neurogenic locus notch homolog protein Hippo: Hippo signaling pathway HNF4A: Hepatocyte nuclear factor 4 alpha HNF1A: Hepatocyte nuclear factor 1 alpha FOXA1/2: Forkhead box protein A1/2 CEBPA: CCAAT/enhancer-binding protein alpha GATA4/6: GATA binding protein 4/6 PROX1: Prospero homeobox protein 1 SOX9: SRY-box transcription factor 9 HNF6/Onecut1: Hepatocyte nuclear factor 6/Onecut homeobox 1 ONECUT2/HNF6β: Onecut homeobox 2/Hepatocyte nuclear factor 6 beta TBX3/18: T-box transcription factor 3/18 miRNA: MicroRNA ERK: Extracellular signal-regulated kinase MAPK: Mitogen-activated protein kinase PI3K: Phosphoinositide 3-kinase AKT: Protein kinase B STAT3: Signal transducer and activator of transcription 3 EGFR: Epidermal growth factor receptor IGF: Insulin-like growth factor HIF: Hypoxia-inducible factor VEGF: Vascular endothelial growth factor ECM: Extracellular matrix ROS: Reactive oxygen species JAK: Janus kinase NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells Declarations Ethics declarations: Ethics approval and consent to participate Not applicable. Consent for publication: Not applicable. Data Availability statement: All data generated or analyzed during this study are included in this article. Competing interests: The authors declare that they have no competing interests. Funding: I declare that there was not any source of funding for this research work. Acknowledgements: “Not applicable”. Authors’ Contribution: Ovais Shafi (OS)* is the author of the study and was involved in the idea, concept, design, and methodology of the study, literature search and references. He did the writing, editing, and revision of the manuscript. He was involved in drawing the findings, results, conclusions, implications of the study, interpretation of the data and was involved in all aspects of the study. He prepared and wrote discussion, results, conclusions and all areas of the study. OS extracted and analyzed the data. He was involved in critical evaluation, audit of every aspect of the study, data extraction, adherence of the study to relevant PRISMA guidelines, limitations of the study, references, and all others. He was involved in drawing fig 1. The author read and approved the manuscript. He investigated hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6β, TBX3/18, Wnt/β-catenin pathway, FGF, HGF, TGF-β, Hippo signaling pathway. Ovais Shafi (OS)* , MBBS - Sindh Medical College - Dow University of Health Sciences, Karachi, Pakistan. He aspires to become an eminent ‘Physician Scientist’. He is devoted to the research in disease development mechanisms, disease origins and therapeutics. OS is also passionate about multiple research areas including clinical trials, clinical medicine, therapeutics, regenerative medicine, precision medicine including gene therapies, finding disease specific targets for gene therapy, role of disease genomics and epigenetics in diagnosis, management, and therapeutics development. He is dedicated to the field of research and clinical medicine. Email address*: [email protected] Corresponding author: OS Correspondence to Ovais Shafi Rahimeen Rajpar (RR) is also the author of the study and contributed to the writing, editing and revision of the study. She also contributed to the results and conclusions of this manuscript along with working on the findings. She contributed to investigating the hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6β, TBX3/18, Wnt/β-catenin pathway, FGF, HGF, TGF-β, Hippo signaling pathway. Rahimeen Rajpar, MD is a dedicated medical professional with a passion for unraveling the mysteries of disease origins and progression. Currently pursuing her residency in internal medicine, RR harbors ambitions of specializing in oncology, with a focus on understanding and treating various forms of cancer. RR's commitment to advancing medical knowledge extends beyond the laboratory, she is working towards becoming a leader in the world of Medicine and Oncology, looking at the medical intricacies from a different lens. Apart from research RR remains dedicated to improving the lives of her patients through comprehensive care and by working towards scientific discoveries. RR is a MBBS graduate from Sindh Medical College – Jinnah Sindh Medical University, Karachi, Pakistan. Shakaib Zafar (SZ) is the co-author of the study. He contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections along with working on references. He contributed to investigating the hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6β, TBX3/18, Wnt/β-catenin pathway, FGF, HGF, TGF-β, Hippo signaling pathway. Dr Shakaib Zafar, MBBS - Sindh Medical College - Dow University of Health Sciences, Karachi, Pakistan. He is currently working at Aga khan University Hospital, after the completion of residency in Anaesthesiology. Areas of Research Interest include disease develop mechanisms and disease origins which are the pillars of the field of Medicine. Saba Irfan (SI) is the co-author of the study. She contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections along with working on references. She contributed to investigating the hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6β, TBX3/18, Wnt/β-catenin pathway, FGF, HGF, TGF-β, Hippo signaling pathway. Saba Irfan MBBS, MD from Columbus, Ohio is an accomplished physician who graduated from Federal Medical and Dental College, Pakistan with extensive clinical experience across Pakistan, Canada, and the USA. Her interests lie in research studies, value-based medicine, and quality improvement initiatives. Currently pursuing a research fellowship affiliated with Michigan State University. Muhammad Ashar (MA) is the co-author of the study. He contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections along with working on references. He contributed to investigating the hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6β, TBX3/18, Wnt/β-catenin pathway, FGF, HGF, TGF-β, Hippo signaling pathway. Muhammad Ashar, MD is a Resident Medical Officer in the Department of General Surgery at Aga Khan University Hospital, Karachi, Pakistan. His research focuses on hepatocellular carcinoma and other gastrointestinal malignancies. He is ECFMG certified and holds a medical license in the United States, with plans to pursue further training and a career in surgical oncology in the US. His research interests include: hepato-pancreato-biliary cancers, gastrointestinal oncology, esophageal cancers, and is currently affiliated with Aga Khan University Hospital, Department of General Surgery, Hepato-Pancreato-Biliary and Surgical Oncology, Karachi, Pakistan. Shah Hussain Jafry (SHJ) is the co-author of the study. He contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections along with working on references. He contributed to investigating the hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6β, TBX3/18, Wnt/β-catenin pathway, FGF, HGF, TGF-β, Hippo signaling pathway. Shah Hussain Jafry, MBBS - Sindh Medical College – Jinnah Sindh Medical University, Karachi, Pakistan. He graduated in 2021 with the hopes of matching in Internal Medicine. He has completed both USMLE Step 1 and 2, and plans to participate in the upcoming match season 2024/25. Areas of research interest include disease development mechanisms and disease origins which are the pillars of the field of medicine. Luqman Naseer Virk (LNV) is the co-author of the study. He contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections along with working on references. He contributed to investigating the hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6β, TBX3/18, Wnt/β-catenin pathway, FGF, HGF, TGF-β, Hippo signaling pathway. Luqman Naseer Virk, MBBS - Sindh Medical College - Dow University of Health Sciences, Karachi, Pakistan. He is a vibrant and talented researcher. Areas of research interest include disease development mechanisms and disease origins which are the pillars of the field of medicine. Raveena (RA) is the co-author of the study. She contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections along with working on references. She contributed to investigating the hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6β, TBX3/18, Wnt/β-catenin pathway, FGF, HGF, TGF-β, Hippo signaling pathway. Raveena, MBBS - Sindh Medical College – Jinnah Sindh Medical University, Karachi, Pakistan. She is passionate about research in surgery and disease development mechanisms including neurodegenerative diseases, oncogenesis and others. She is ECFMG Certified. She is passionate about residency in Internal Medicine/Surgery. Her goal is to make significant impact in the field of Research. The work and contributions of everyone have been described in detail, the order is randomized and the numbering is just for referencing purpose. References Balogh J, Victor D 3rd, Asham EH, Burroughs SG, Boktour M, Saharia A, Li X, Ghobrial RM, Monsour HP Jr. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma. 2016 Oct 5;3:41-53. doi: 10.2147/JHC.S61146. PMID: 27785449; PMCID: PMC5063561. Llovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021 Jan 21;7(1):6. doi: 10.1038/s41572-020-00240-3. Erratum in: Nat Rev Dis Primers. 2024 Feb 12;10(1):10. PMID: 33479224. Vogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet. 2022 Oct 15;400(10360):1345-1362. doi: 10.1016/S0140-6736(22)01200-4. Epub 2022 Sep 6. PMID: 36084663. Schulze RJ, Schott MB, Casey CA, Tuma PL, McNiven MA. The cell biology of the hepatocyte: A membrane trafficking machine. J Cell Biol. 2019 Jul 1;218(7):2096-2112. doi: 10.1083/jcb.201903090. Epub 2019 Jun 14. PMID: 31201265; PMCID: PMC6605791. Shin D, Monga SP. Cellular and molecular basis of liver development. Compr Physiol. 2013 Apr;3(2):799-815. doi: 10.1002/cphy.c120022. PMID: 23720330; PMCID: PMC4445238. Ober EA, Lemaigre FP. Development of the liver: Insights into organ and tissue morphogenesis. J Hepatol. 2018 May;68(5):1049-1062. doi: 10.1016/j.jhep.2018.01.005. Epub 2018 Jan 13. PMID: 29339113. Suresh A, Dhanasekaran R. Implications of genetic heterogeneity in hepatocellular cancer. Adv Cancer Res. 2022;156:103-135. doi: 10.1016/bs.acr.2022.01.007. Epub 2022 Mar 7. PMID: 35961697; PMCID: PMC10321863. Lu LC, Hsu CH, Hsu C, Cheng AL. Tumor Heterogeneity in Hepatocellular Carcinoma: Facing the Challenges. Liver Cancer. 2016 Apr;5(2):128-38. doi: 10.1159/000367754. Epub 2016 Mar 17. PMID: 27386431; PMCID: PMC4906428. Kalasekar SM, VanSant-Webb CH, Evason KJ. Intratumor Heterogeneity in Hepatocellular Carcinoma: Challenges and Opportunities. Cancers (Basel). 2021 Nov 3;13(21):5524. doi: 10.3390/cancers13215524. PMID: 34771685; PMCID: PMC8582820. Friemel J, Rechsteiner M, Frick L, Böhm F, Struckmann K, Egger M, Moch H, Heikenwalder M, Weber A. Intratumor heterogeneity in hepatocellular carcinoma. Clin Cancer Res. 2015 Apr 15;21(8):1951-61. doi: 10.1158/1078-0432.CCR-14-0122. Epub 2014 Sep 23. PMID: 25248380. Safri F, Nguyen R, Zerehpooshnesfchi S, George J, Qiao L. Heterogeneity of hepatocellular carcinoma: from mechanisms to clinical implications. Cancer Gene Ther. 2024 Mar 18. doi: 10.1038/s41417-024-00764-w. Epub ahead of print. PMID: 38499648. Cabillic F, Corlu A. Regulation of Transdifferentiation and Retrodifferentiation by Inflammatory Cytokines in Hepatocellular Carcinoma. Gastroenterology. 2016 Oct;151(4):607-15. doi: 10.1053/j.gastro.2016.06.052. Epub 2016 Jul 19. PMID: 27443822. Cerec V, Glaise D, Garnier D, Morosan S, Turlin B, Drenou B, Gripon P, Kremsdorf D, Guguen-Guillouzo C, Corlu A. Transdifferentiation of hepatocyte-like cells from the human hepatoma HepaRG cell line through bipotent progenitor. Hepatology. 2007 Apr;45(4):957-67. doi: 10.1002/hep.21536. PMID: 17393521. Hughes A, Dhoot GK. Dysregulated cancer cell transdifferentiation into erythrocytes is an additional metabolic stress in hepatocellular carcinoma. Tumour Biol. 2018 Nov;40(11):1010428318811467. doi: 10.1177/1010428318811467. PMID: 30419801. Shen CN, Slack JM, Tosh D. Molecular basis of transdifferentiation of pancreas to liver. Nat Cell Biol. 2000 Dec;2(12):879-87. doi: 10.1038/35046522. PMID: 11146651. Meindl-Beinker NM, Dooley S. Transforming growth factor-beta and hepatocyte transdifferentiation in liver fibrogenesis. J Gastroenterol Hepatol. 2008 Mar;23 Suppl 1:S122-7. doi: 10.1111/j.1440-1746.2007.05297.x. PMID: 18336655. DeLaForest A, Nagaoka M, Si-Tayeb K, Noto FK, Konopka G, Battle MA, Duncan SA. HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells. Development. 2011 Oct;138(19):4143-53. doi: 10.1242/dev.062547. Epub 2011 Aug 18. PMID: 21852396; PMCID: PMC3171218. Parviz F, Matullo C, Garrison WD, Savatski L, Adamson JW, Ning G, Kaestner KH, Rossi JM, Zaret KS, Duncan SA. Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet. 2003 Jul;34(3):292-6. doi: 10.1038/ng1175. PMID: 12808453. Marable SS, Chung E, Park JS. Hnf4a Is Required for the Development of Cdh6-Expressing Progenitors into Proximal Tubules in the Mouse Kidney. J Am Soc Nephrol. 2020 Nov;31(11):2543-2558. doi: 10.1681/ASN.2020020184. Epub 2020 Aug 6. PMID: 32764140; PMCID: PMC7608976. Yoshimura Y, Muto Y, Omachi K, Miner JH, Humphreys BD. Elucidating the Proximal Tubule HNF4A Gene Regulatory Network in Human Kidney Organoids. J Am Soc Nephrol. 2023 Oct 1;34(10):1672-1686. doi: 10.1681/ASN.0000000000000197. Epub 2023 Jul 25. PMID: 37488681; PMCID: PMC10561821. Chen L, Toke NH, Luo S, Vasoya RP, Aita R, Parthasarathy A, Tsai YH, Spence JR, Verzi MP. HNF4 factors control chromatin accessibility and are redundantly required for maturation of the fetal intestine. Development. 2019 Aug 6;146(19):dev179432. doi: 10.1242/dev.179432. PMID: 31345929; PMCID: PMC6803367. Kaci A, Solheim MH, Silgjerd T, Hjaltadottir J, Hornnes LH, Molnes J, Madsen A, Sjøholt G, Bellanné-Chantelot C, Caswell R, Sagen JV, Njølstad PR, Aukrust I, Bjørkhaug L. Functional characterization of HNF4A gene variants identify promoter and cell line specific transactivation effects. Hum Mol Genet. 2024 Mar 3:ddae027. doi: 10.1093/hmg/ddae027. Epub ahead of print. PMID: 38433330. Lei X, Ketelut-Carneiro N, Shmuel-Galia L, Xu W, Wilson R, Vierbuchen T, Chen Y, Reboldi A, Kang J, Edelblum KL, Ward D, Fitzgerald KA. Epithelial HNF4A shapes the intraepithelial lymphocyte compartment via direct regulation of immune signaling molecules. J Exp Med. 2022 Aug 1;219(8):e20212563. doi: 10.1084/jem.20212563. Epub 2022 Jul 6. PMID: 35792863; PMCID: PMC9263552. Michelson DA, Zuo C, Verzi M, Benoist C, Mathis D. Hnf4 activates mimetic-cell enhancers to recapitulate gut and liver development within the thymus. J Exp Med. 2023 Oct 2;220(10):e20230461. doi: 10.1084/jem.20230461. Epub 2023 Jul 3. PMID: 37399024; PMCID: PMC10318407. Dubois V, Staels B, Lefebvre P, Verzi MP, Eeckhoute J. Control of Cell Identity by the Nuclear Receptor HNF4 in Organ Pathophysiology. Cells. 2020 Sep 28;9(10):2185. doi: 10.3390/cells9102185. PMID: 32998360; PMCID: PMC7600215. Ma HM, Zhang Q, Yang XM, Hu Y, Zhang J, Chen L, Zhao B, Yang WT, Xu R. HNF4A Regulates the Proliferation and Tumor Formation of Cervical Cancer Cells through the Wnt/ β -Catenin Pathway. Oxid Med Cell Longev. 2022 Jan 28;2022:8168988. doi: 10.1155/2022/8168988. PMID: 35132353; PMCID: PMC8817108. Vuong LM, Chellappa K, Dhahbi JM, Deans JR, Fang B, Bolotin E, Titova NV, Hoverter NP, Spindler SR, Waterman ML, Sladek FM. Differential Effects of Hepatocyte Nuclear Factor 4α Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells. Mol Cell Biol. 2015 Oct;35(20):3471-90. doi: 10.1128/MCB.00030-15. Epub 2015 Aug 3. PMID: 26240283; PMCID: PMC4573706. Sugai M, Umezu H, Yamamoto T, Jiang S, Iwanari H, Tanaka T, Hamakubo T, Kodama T, Naito M. Expression of hepatocyte nuclear factor 4 alpha in primary ovarian mucinous tumors. Pathol Int. 2008 Nov;58(11):681-6. doi: 10.1111/j.1440-1827.2008.02293.x. PMID: 18844932. Ma HM, Zhang Q, Yang XM, Hu Y, Zhang J, Chen L, Zhao B, Yang WT, Xu R. HNF4A Regulates the Proliferation and Tumor Formation of Cervical Cancer Cells through the Wnt/ β -Catenin Pathway. Oxid Med Cell Longev. 2022 Jan 28;2022:8168988. doi: 10.1155/2022/8168988. PMID: 35132353; PMCID: PMC8817108. Wang Z, Li Y, Wu D, Yu S, Wang Y, Leung Chan F. Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence. Oncogene. 2020 Feb;39(7):1572-1589. doi: 10.1038/s41388-019-1080-3. Epub 2019 Nov 6. Erratum in: Oncogene. 2020 Sep;39(39):6263. PMID: 31695151; PMCID: PMC7018660. Ning BF, Ding J, Yin C, Zhong W, Wu K, Zeng X, Yang W, Chen YX, Zhang JP, Zhang X, Wang HY, Xie WF. Hepatocyte nuclear factor 4 alpha suppresses the development of hepatocellular carcinoma. Cancer Res. 2010 Oct 1;70(19):7640-51. doi: 10.1158/0008-5472.CAN-10-0824. Epub 2010 Sep 28. PMID: 20876809. Shokouhian B, Negahdari B, Heydari Z, Totonchi M, Aboulkheyr Es H, Piryaei A, Mostafavi E, Vosough M. HNF4α is possibly the missing link between epithelial-mesenchymal transition and Warburg effect during hepatocarcinogenesis. Cancer Sci. 2023 Apr;114(4):1337-1352. doi: 10.1111/cas.15686. Epub 2022 Dec 19. PMID: 36479791; PMCID: PMC10067433. Suresh A, Dhanasekaran R. Implications of genetic heterogeneity in hepatocellular cancer. Adv Cancer Res. 2022;156:103-135. doi: 10.1016/bs.acr.2022.01.007. Epub 2022 Mar 7. PMID: 35961697; PMCID: PMC10321863. Sang L, Wang X, Bai W, Shen J, Zeng Y, Sun J. The role of hepatocyte nuclear factor 4α (HNF4α) in tumorigenesis. Front Oncol. 2022 Sep 28;12:1011230. doi: 10.3389/fonc.2022.1011230. PMID: 36249028; PMCID: PMC9554155. Xu L, Hui L, Wang S, Gong J, Jin Y, Wang Y, Ji Y, Wu X, Han Z, Hu G. Expression profiling suggested a regulatory role of liver-enriched transcription factors in human hepatocellular carcinoma. Cancer Res. 2001 Apr 1;61(7):3176-81. PMID: 11306505. Désert R, Nieto N, Musso O. Dimensions of hepatocellular carcinoma phenotypic diversity. World J Gastroenterol. 2018 Oct 28;24(40):4536-4547. doi: 10.3748/wjg.v24.i40.4536. PMID: 30386103; PMCID: PMC6209578. Miyachi Y, Miyazawa T, Ogawa Y. HNF1A Mutations and Beta Cell Dysfunction in Diabetes. Int J Mol Sci. 2022 Mar 16;23(6):3222. doi: 10.3390/ijms23063222. PMID: 35328643; PMCID: PMC8948720. Li LM, Jiang BG, Sun LL. HNF1A：From Monogenic Diabetes to Type 2 Diabetes and Gestational Diabetes Mellitus. Front Endocrinol (Lausanne). 2022 Mar 1;13:829565. doi: 10.3389/fendo.2022.829565. PMID: 35299962; PMCID: PMC8921476. Qian MF, Bevacqua RJ, Coykendall VM, Liu X, Zhao W, Chang CA, Gu X, Dai XQ, MacDonald PE, Kim SK. HNF1α maintains pancreatic α and β cell functions in primary human islets. JCI Insight. 2023 Dec 22;8(24):e170884. doi: 10.1172/jci.insight.170884. PMID: 37943614; PMCID: PMC10807710. Kavitha B, Ranganathan S, Gopi S, Vetrivel U, Hemavathy N, Mohan V, Radha V. Molecular characterization and re-interpretation of HNF1A variants identified in Indian MODY subjects towards precision medicine. Front Endocrinol (Lausanne). 2023 Jun 16;14:1177268. doi: 10.3389/fendo.2023.1177268. PMID: 37396188; PMCID: PMC10313120. Sepehri Z, Banerjee A, Vizeacoumar FS, Freywald A, Vizeacoumar FJ, Dolinsky VW, Davie JR. Differential expression of HNF1A and HNF1A-AS1 in colon cancer cells. IUBMB Life. 2022 Jun;74(6):496-507. doi: 10.1002/iub.2609. Epub 2022 Mar 2. PMID: 35184384. DeForest N, Kavitha B, Hu S, Isaac R, Krohn L, Wang M, Du X, De Arruda Saldanha C, Gylys J, Merli E, Abagyan R, Najmi L, Mohan V; Alnylam Human Genetics; AMP-T2D Consortium; Flannick J, Peloso GM, Gordts PLSM, Heinz S, Deaton AM, Khera AV, Olefsky J, Radha V, Majithia AR. Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of atherogenic lipoproteins. Cell Genom. 2023 May 30;3(7):100339. doi: 10.1016/j.xgen.2023.100339. PMID: 37492105; PMCID: PMC10363808. Najmi LA, Aukrust I, Flannick J, Molnes J, Burtt N, Molven A, Groop L, Altshuler D, Johansson S, Bjørkhaug L, Njølstad PR. Functional Investigations of HNF1A Identify Rare Variants as Risk Factors for Type 2 Diabetes in the General Population. Diabetes. 2017 Feb;66(2):335-346. doi: 10.2337/db16-0460. Epub 2016 Nov 29. PMID: 27899486; PMCID: PMC5860263. Luo Z, Li Y, Wang H, Fleming J, Li M, Kang Y, Zhang R, Li D. Hepatocyte nuclear factor 1A (HNF1A) as a possible tumor suppressor in pancreatic cancer. PLoS One. 2015 Mar 20;10(3):e0121082. doi: 10.1371/journal.pone.0121082. PMID: 25793983; PMCID: PMC4368635. Liu Y, Zhao F, Tan F, Tang L, Du Z, Mou J, Zhou G, Yuan C. HNF1A-AS1: A Tumor-associated Long Non-coding RNA. Curr Pharm Des. 2022;28(21):1720-1729. doi: 10.2174/1381612828666220520113846. PMID: 35619319. Cai C, Bi D, Bick G, Wei Q, Liu H, Lu L, Zhang X, Qin H. Hepatocyte nuclear factor HNF1A is a potential regulator in shaping the super-enhancer landscape in colorectal cancer liver metastasis. FEBS Lett. 2021 Dec;595(24):3056-3071. doi: 10.1002/1873-3468.14219. Epub 2021 Nov 22. PMID: 34719039. Abel EV, Goto M, Magnuson B, Abraham S, Ramanathan N, Hotaling E, Alaniz AA, Kumar-Sinha C, Dziubinski ML, Urs S, Wang L, Shi J, Waghray M, Ljungman M, Crawford HC, Simeone DM. HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties. Elife. 2018 Aug 3;7:e33947. doi: 10.7554/eLife.33947. PMID: 30074477; PMCID: PMC6122955. Fujino S, Miyoshi N, Ito A, Yasui M, Matsuda C, Ohue M, Uemura M, Mizushima T, Doki Y, Eguchi H. HNF1A regulates colorectal cancer progression and drug resistance as a downstream of POU5F1. Sci Rep. 2021 May 14;11(1):10363. doi: 10.1038/s41598-021-89126-2. PMID: 33990627; PMCID: PMC8121855. Schulze K, Zucman-Rossi J. Current issues on genomic heterogeneity in hepatocellular carcinoma and its implication in clinical practice. Hepat Oncol. 2015 Jul;2(3):291-302. doi: 10.2217/hep.15.16. Epub 2015 Jul 27. PMID: 30191009; PMCID: PMC6095162. Jin K, Lan H, Wang X, Lv J. Genetic heterogeneity in hepatocellular carcinoma and paired bone metastasis revealed by next-generation sequencing. Int J Clin Exp Pathol. 2017 Oct 1;10(10):10495-10504. PMID: 31966388; PMCID: PMC6965764. McGlacken-Byrne SM, Mohammad JK, Conlon N, Gubaeva D, Siersbæk J, Schou AJ, Demirbilek H, Dastamani A, Houghton JAL, Brusgaard K, Melikyan M, Christesen H, Flanagan SE, Murphy NP, Shah P. Clinical and genetic heterogeneity of HNF4A/HNF1A mutations in a multicentre paediatric cohort with hyperinsulinaemic hypoglycaemia. Eur J Endocrinol. 2022 Feb 22;186(4):417-427. doi: 10.1530/EJE-21-0897. PMID: 35089870. Hechtman JF, Abou-Alfa GK, Stadler ZK, Mandelker DL, Roehrl MHA, Zehir A, Vakiani E, Middha S, Klimstra DS, Shia J. Somatic HNF1A mutations in the malignant transformation of hepatocellular adenomas: a retrospective analysis of data from MSK-IMPACT and TCGA. Hum Pathol. 2019 Jan;83:1-6. doi: 10.1016/j.humpath.2018.08.004. Epub 2018 Aug 17. PMID: 30121369; PMCID: PMC6365190. Barcena-Varela M, Lujambio A. The Endless Sources of Hepatocellular Carcinoma Heterogeneity. Cancers (Basel). 2021 May 26;13(11):2621. doi: 10.3390/cancers13112621. PMID: 34073538; PMCID: PMC8198457. Friedman JR, Kaestner KH. The Foxa family of transcription factors in development and metabolism. Cell Mol Life Sci. 2006 Oct;63(19-20):2317-28. doi: 10.1007/s00018-006-6095-6. PMID: 16909212. Geusz RJ, Wang A, Lam DK, Vinckier NK, Alysandratos KD, Roberts DA, Wang J, Kefalopoulou S, Ramirez A, Qiu Y, Chiou J, Gaulton KJ, Ren B, Kotton DN, Sander M. Sequence logic at enhancers governs a dual mechanism of endodermal organ fate induction by FOXA pioneer factors. Nat Commun. 2021 Nov 17;12(1):6636. doi: 10.1038/s41467-021-26950-0. PMID: 34789735; PMCID: PMC8599738. Lan Q, Cao M, Kollipara RK, Rosa JB, Kittler R, Jiang H. FoxA transcription factor Fork head maintains the intestinal stem/progenitor cell identities in Drosophila. Dev Biol. 2018 Jan 15;433(2):324-343. doi: 10.1016/j.ydbio.2017.09.002. Epub 2017 Nov 3. PMID: 29108672. Heslop JA, Duncan SA. FoxA factors: the chromatin key and doorstop essential for liver development and function. Genes Dev. 2020 Aug 1;34(15-16):1003-1004. doi: 10.1101/gad.340570.120. PMID: 32747476; PMCID: PMC7397850. Fournier M, Bourriquen G, Lamaze FC, Côté MC, Fournier É, Joly-Beauparlant C, Caron V, Gobeil S, Droit A, Bilodeau S. FOXA and master transcription factors recruit Mediator and Cohesin to the core transcriptional regulatory circuitry of cancer cells. Sci Rep. 2016 Oct 14;6:34962. doi: 10.1038/srep34962. PMID: 27739523; PMCID: PMC5064413. Huang C, Liu J, Xiong B, Yonemura Y, Yang X. Expression and prognosis analyses of forkhead box A (FOXA) family in human lung cancer. Gene. 2019 Feb 15;685:202-210. doi: 10.1016/j.gene.2018.11.022. Epub 2018 Nov 9. PMID: 30415009. Mirosevich J, Gao N, Gupta A, Shappell SB, Jove R, Matusik RJ. Expression and role of Foxa proteins in prostate cancer. Prostate. 2006 Jul 1;66(10):1013-28. doi: 10.1002/pros.20299. PMID: 16001449. Arruabarrena-Aristorena A, Maag JLV, Kittane S, Cai Y, Karthaus WR, Ladewig E, Park J, Kannan S, Ferrando L, Cocco E, Ho SY, Tan DS, Sallaku M, Wu F, Acevedo B, Selenica P, Ross DS, Witkin M, Sawyers CL, Reis-Filho JS, Verma CS, Jauch R, Koche R, Baselga J, Razavi P, Toska E, Scaltriti M. FOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer. Cancer Cell. 2020 Oct 12;38(4):534-550.e9. doi: 10.1016/j.ccell.2020.08.003. Epub 2020 Sep 3. PMID: 32888433; PMCID: PMC8311901. Wolf I, Bose S, Williamson EA, Miller CW, Karlan BY, Koeffler HP. FOXA1: Growth inhibitor and a favorable prognostic factor in human breast cancer. Int J Cancer. 2007 Mar 1;120(5):1013-22. doi: 10.1002/ijc.22389. PMID: 17163418. Katoh M, Igarashi M, Fukuda H, Nakagama H, Katoh M. Cancer genetics and genomics of human FOX family genes. Cancer Lett. 2013 Jan 28;328(2):198-206. doi: 10.1016/j.canlet.2012.09.017. Epub 2012 Sep 27. PMID: 23022474. Gong Z, Yu J, Yang S, Lai PBS, Chen GG. FOX transcription factor family in hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer. 2020 Aug;1874(1):188376. doi: 10.1016/j.bbcan.2020.188376. Epub 2020 May 11. PMID: 32437734. Li Z, Tuteja G, Schug J, Kaestner KH. Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell. 2012 Jan 20;148(1-2):72-83. doi: 10.1016/j.cell.2011.11.026. PMID: 22265403; PMCID: PMC3266536. Ouyang X, Feng L, Yao L, Zhang J, Xiao Y, Liu G, Zhang G, Wang Z. A comprehensive analysis of FOX family in HCC and experimental evidence to support the oncogenic role of FOXH1. Aging (Albany NY). 2022 Mar 7;14(5):2268-2286. doi: 10.18632/aging.203934. Epub 2022 Mar 7. PMID: 35255005; PMCID: PMC8954963. Keng VW, Largaespada DA, Villanueva A. Why men are at higher risk for hepatocellular carcinoma? J Hepatol. 2012 Aug;57(2):453-4. doi: 10.1016/j.jhep.2012.03.004. Epub 2012 Mar 13. PMID: 22425699; PMCID: PMC3506003. Zhao Y, Li Z. Interplay of estrogen receptors and FOXA factors in the liver cancer. Mol Cell Endocrinol. 2015 Dec 15;418 Pt 3(0 3):334-9. doi: 10.1016/j.mce.2015.01.043. Epub 2015 Feb 4. PMID: 25661537; PMCID: PMC4524798. Luo Q, Wang CQ, Yang LY, Gao XM, Sun HT, Zhang Y, Zhang KL, Zhu Y, Zheng Y, Sheng YY, Lu L, Jia HL, Yu WQ, Liu J, Dong QZ, Qin LX. FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk between fibroblasts and tumor cells. Cancer Lett. 2018 Mar 28;417:21-34. doi: 10.1016/j.canlet.2017.12.021. Epub 2017 Dec 15. PMID: 29248714. Xia L, Huang W, Tian D, Zhu H, Qi X, Chen Z, Zhang Y, Hu H, Fan D, Nie Y, Wu K. Overexpression of forkhead box C1 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma. Hepatology. 2013 Feb;57(2):610-24. doi: 10.1002/hep.26029. PMID: 22911555. Kalinichenko VV, Major ML, Wang X, Petrovic V, Kuechle J, Yoder HM, Dennewitz MB, Shin B, Datta A, Raychaudhuri P, Costa RH. Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Genes Dev. 2004 Apr 1;18(7):830-50. doi: 10.1101/gad.1200704. PMID: 15082532; PMCID: PMC387422. Da BL, Suchman KI, Lau L, Rabiee A, He AR, Shetty K, Yu H, Wong LL, Amdur RL, Crawford JM, Fox SS, Grimaldi GM, Shah PK, Weinstein J, Bernstein D, Satapathy SK, Chambwe N, Xiang X, Mishra L. Pathogenesis to management of hepatocellular carcinoma. Genes Cancer. 2022 Dec 13;13:72-87. doi: 10.18632/genesandcancer.226. PMID: 36533190; PMCID: PMC9746873. Wang J, Zhu CP, Hu PF, Qian H, Ning BF, Zhang Q, Chen F, Liu J, Shi B, Zhang X, Xie WF. FOXA2 suppresses the metastasis of hepatocellular carcinoma partially through matrix metalloproteinase-9 inhibition. Carcinogenesis. 2014 Nov;35(11):2576-83. doi: 10.1093/carcin/bgu180. Epub 2014 Aug 20. PMID: 25142974. Quintana-Bustamante O, Lan-Lan Smith S, Griessinger E, Reyal Y, Vargaftig J, Lister TA, Fitzgibbon J, Bonnet D. Overexpression of wild-type or mutants forms of CEBPA alter normal human hematopoiesis. Leukemia. 2012 Jul;26(7):1537-46. doi: 10.1038/leu.2012.38. Epub 2012 Feb 10. PMID: 22371011; PMCID: PMC3378638. Leecharendkeat A, Tocharoentanaphol C, Auewarakul CU. CCAAT/enhancer binding protein-alpha polymorphisms occur more frequently than mutations in acute myeloid leukemia and exist across all cytogenetic risk groups and leukemia subtypes. Int J Cancer. 2008 Nov 15;123(10):2321-6. doi: 10.1002/ijc.23796. PMID: 18729193. Rázga F, Dvoráková D, Jurcek T, Jezísková I, Krístková Z, Mayer J. CEBPA gene mutational status: a complete screening using high-resolution melt curve analysis. Mol Diagn Ther. 2009;13(3):195-200. doi: 10.2165/01250444-200913030-00004. PMID: 19650672. Wilhelmson AS, Porse BT. CCAAT enhancer binding protein alpha (CEBPA) biallelic acute myeloid leukaemia: cooperating lesions, molecular mechanisms and clinical relevance. Br J Haematol. 2020 Aug;190(4):495-507. doi: 10.1111/bjh.16534. Epub 2020 Feb 21. PMID: 32086816; PMCID: PMC7496298. Hollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters ST, Zimmermann M, Peeters JK, Valk PJ, Balgobind BV, Sonneveld E, Kaspers GJ, de Bont ES, Trka J, Baruchel A, Creutzig U, Pieters R, Reinhardt D, Zwaan CM. Characterization of CEBPA mutations and promoter hypermethylation in pediatric acute myeloid leukemia. Haematologica. 2011 Mar;96(3):384-92. doi: 10.3324/haematol.2010.031336. Epub 2010 Dec 6. PMID: 21134981; PMCID: PMC3046269. Kantzer CG, Yang W, Grommisch D, Vikhe Patil K, Mak KH, Shirokova V, Genander M. ID1 and CEBPA coordinate epidermal progenitor cell differentiation. Development. 2022 Nov 15;149(22):dev201262. doi: 10.1242/dev.201262. Epub 2022 Nov 16. PMID: 36330928; PMCID: PMC9845743. Chen X, Zhou W, Song RH, Liu S, Wang S, Chen Y, Gao C, He C, Xiao J, Zhang L, Wang T, Liu P, Duan K, Cheng Z, Zhang C, Zhang J, Sun Y, Jackson F, Lan F, Liu Y, Xu Y, Wong JJ, Wang P, Yang H, Xiong Y, Chen T, Li Y, Ye D. Tumor suppressor CEBPA interacts with and inhibits DNMT3A activity. Sci Adv. 2022 Jan 28;8(4):eabl5220. doi: 10.1126/sciadv.abl5220. Epub 2022 Jan 26. PMID: 35080973; PMCID: PMC8791617. Ellsworth PN, Herring JA, Leifer AH, Ray JD, Elison WS, Poulson PD, Crabtree JE, Van Ry PM, Tessem JS. CEBPA Overexpression Enhances β-Cell Proliferation and Survival. Biology (Basel). 2024 Feb 9;13(2):110. doi: 10.3390/biology13020110. PMID: 38392328; PMCID: PMC10887016. Setten RL, Lightfoot HL, Habib NA, Rossi JJ. Development of MTL-CEBPA: Small Activating RNA Drug for Hepatocellular Carcinoma. Curr Pharm Biotechnol. 2018;19(8):611-621. doi: 10.2174/1389201019666180611093428. PMID: 29886828; PMCID: PMC6204661. Huang KW, Tan CP, Reebye V, Chee CE, Zacharoulis D, Habib R, Blakey DC, Rossi JJ, Habib N, Sodergren MH. MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models. Int J Mol Sci. 2021 Aug 25;22(17):9168. doi: 10.3390/ijms22179168. PMID: 34502076; PMCID: PMC8431011. Wang C, Ren R, Hu H, Tan C, Han M, Wang X, Zheng Y. MiR-182 is up-regulated and targeting Cebpa in hepatocellular carcinoma. Chin J Cancer Res. 2014 Feb;26(1):17-29. doi: 10.3978/j.issn.1000-9604.2014.01.01. PMID: 24653623; PMCID: PMC3937760. Reebye V, Huang KW, Lin V, Jarvis S, Cutilas P, Dorman S, Ciriello S, Andrikakou P, Voutila J, Saetrom P, Mintz PJ, Reccia I, Rossi JJ, Huber H, Habib R, Kostomitsopoulos N, Blakey DC, Habib NA. Gene activation of CEBPA using saRNA: preclinical studies of the first in human saRNA drug candidate for liver cancer. Oncogene. 2018 Jun;37(24):3216-3228. doi: 10.1038/s41388-018-0126-2. Epub 2018 Mar 7. PMID: 29511346; PMCID: PMC6013054. Lu GD, Leung CH, Yan B, Tan CM, Low SY, Aung MO, Salto-Tellez M, Lim SG, Hooi SC. C/EBPalpha is up-regulated in a subset of hepatocellular carcinomas and plays a role in cell growth and proliferation. Gastroenterology. 2010 Aug;139(2):632-43, 643.e1-4. doi: 10.1053/j.gastro.2010.03.051. Epub 2010 Mar 27. PMID: 20347819. Harigae H. GATA transcription factors and hematological diseases. Tohoku J Exp Med. 2006 Sep;210(1):1-9. doi: 10.1620/tjem.210.1. PMID: 16960339. Katsumura KR, Bresnick EH; GATA Factor Mechanisms Group. The GATA factor revolution in hematology. Blood. 2017 Apr 13;129(15):2092-2102. doi: 10.1182/blood-2016-09-687871. Epub 2017 Feb 8. PMID: 28179282; PMCID: PMC5391619. Lentjes MH, Niessen HE, Akiyama Y, de Bruïne AP, Melotte V, van Engeland M. The emerging role of GATA transcription factors in development and disease. Expert Rev Mol Med. 2016 Mar 8;18:e3. doi: 10.1017/erm.2016.2. PMID: 26953528; PMCID: PMC4836206. Fujiwara T. GATA Transcription Factors: Basic Principles and Related Human Disorders. Tohoku J Exp Med. 2017 Jun;242(2):83-91. doi: 10.1620/tjem.242.83. PMID: 28566565. Barrett DM, Gustafson KS, Wang J, Wang SZ, Ginder GD. A GATA factor mediates cell type-restricted induction of HLA-E gene transcription by gamma interferon. Mol Cell Biol. 2004 Jul;24(14):6194-204. doi: 10.1128/MCB.24.14.6194-6204.2004. PMID: 15226423; PMCID: PMC434230. Keller T, Thompson CR. Cell type specificity of a diffusible inducer is determined by a GATA family transcription factor. Development. 2008 May;135(9):1635-45. doi: 10.1242/dev.020883. Epub 2008 Mar 26. PMID: 18367552; PMCID: PMC3942654. Zheng R, Blobel GA. GATA Transcription Factors and Cancer. Genes Cancer. 2010 Dec;1(12):1178-88. doi: 10.1177/1947601911404223. PMID: 21779441; PMCID: PMC3092280. Khazaeli Najafabadi M, Mirzaeian E, Memar Montazerin S, Tavangar AR, Tabary M, Tavangar SM. Role of GATA3 in tumor diagnosis: A review. Pathol Res Pract. 2021 Oct;226:153611. doi: 10.1016/j.prp.2021.153611. Epub 2021 Sep 13. PMID: 34547599. Parviainen H, Kiiveri S, Bielinska M, Rahman N, Huhtaniemi IT, Wilson DB, Heikinheimo M. GATA transcription factors in adrenal development and tumors. Mol Cell Endocrinol. 2007 Feb;265-266:17-22. doi: 10.1016/j.mce.2006.12.033. Epub 2007 Jan 5. PMID: 17207921. Chou J, Provot S, Werb Z. GATA3 in development and cancer differentiation: cells GATA have it! J Cell Physiol. 2010 Jan;222(1):42-9. doi: 10.1002/jcp.21943. PMID: 19798694; PMCID: PMC2915440. Gonzalez RS, Wang J, Kraus T, Sullivan H, Adams AL, Cohen C. GATA-3 expression in male and female breast cancers: comparison of clinicopathologic parameters and prognostic relevance. Hum Pathol. 2013 Jun;44(6):1065-70. doi: 10.1016/j.humpath.2012.09.010. Epub 2012 Dec 23. PMID: 23266442. Oda H, Hedayati E, Lindström A, Shabo I. GATA-3 expression in breast cancer is related to intratumoral M2 macrophage infiltration and tumor differentiation. PLoS One. 2023 Mar 30;18(3):e0283003. doi: 10.1371/journal.pone.0283003. PMID: 36996051; PMCID: PMC10062580. Enane FO, Shuen WH, Gu X, Quteba E, Przychodzen B, Makishima H, Bodo J, Ng J, Chee CL, Ba R, Seng Koh L, Lim J, Cheong R, Teo M, Hu Z, Ng KP, Maciejewski J, Radivoyevitch T, Chung A, Ooi LL, Tan YM, Cheow PC, Chow P, Chan CY, Lim KH, Yerian L, Hsi E, Toh HC, Saunthararajah Y. GATA4 loss of function in liver cancer impedes precursor to hepatocyte transition. J Clin Invest. 2017 Sep 1;127(9):3527-3542. doi: 10.1172/JCI93488. Epub 2017 Jul 31. PMID: 28758902; PMCID: PMC5669578. Soini T, Haveri H, Elo JM, Kauppinen M, Kyrönlahti A, Salo MK, Lohi J, Andersson LC, Wilson DB, Heikinheimo M. Transcription factor GATA-4 is abundantly expressed in childhood but not in adult liver tumors. J Pediatr Gastroenterol Nutr. 2012 Jan;54(1):101-8. doi: 10.1097/MPG.0b013e31822d52cf. PMID: 21788913. Chen P, Liu X, Liu Y, Bao X, Wu Q. ARHGAP18 is Upregulated by Transcription Factor GATA1 Promotes the Proliferation and Invasion in Hepatocellular Carcinoma. Appl Biochem Biotechnol. 2024 Feb;196(2):679-689. doi: 10.1007/s12010-023-04459-0. Epub 2023 May 12. PMID: 37171759. Tan HW, Leung CO, Chan KK, Ho DW, Leung MS, Wong CM, Ng IO, Lo RC. Deregulated GATA6 modulates stem cell-like properties and metabolic phenotype in hepatocellular carcinoma. Int J Cancer. 2019 Oct 1;145(7):1860-1873. doi: 10.1002/ijc.32248. Epub 2019 Mar 28. PMID: 30834518. Sun W, Zhang Y, Wong KC, Liu K, Yang Y, Wu B, Tong JHM, Chan AWH, Chan HLY, Yu J. Increased expression of GATA zinc finger domain containing 1 through gene amplification promotes liver cancer by directly inducing phosphatase of regenerating liver 3. Hepatology. 2018 Jun;67(6):2302-2319. doi: 10.1002/hep.29750. Epub 2018 Mar 23. PMID: 29266303; PMCID: PMC6001784. Lv X, Xiang X, Wu Y, Liu Y, Xu R, Xiang Q, Lai G. GATA binding protein 4 promotes the expression and transcription of hepatitis B virus by facilitating hepatocyte nuclear factor 4 alpha in vitro. Virol J. 2021 Sep 28;18(1):196. doi: 10.1186/s12985-021-01668-z. PMID: 34583732; PMCID: PMC8479913. Kivelä R, Salmela I, Nguyen YH, Petrova TV, Koistinen HA, Wiener Z, Alitalo K. The transcription factor Prox1 is essential for satellite cell differentiation and muscle fibre-type regulation. Nat Commun. 2016 Oct 12;7:13124. doi: 10.1038/ncomms13124. PMID: 27731315; PMCID: PMC5064023. Gizaw NY, Kallio P, Punger T, Gucciardo E, Haglund C, Böhling T, Lehti K, Sampo M, Alitalo K, Kivelä R. PROX1 transcription factor controls rhabdomyosarcoma growth, stemness, myogenic properties and therapeutic targets. Proc Natl Acad Sci U S A. 2022 Dec 6;119(49):e2116220119. doi: 10.1073/pnas.2116220119. Epub 2022 Dec 2. PMID: 36459642; PMCID: PMC9894179. Hong YK, Harvey N, Noh YH, Schacht V, Hirakawa S, Detmar M, Oliver G. Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn. 2002 Nov;225(3):351-7. doi: 10.1002/dvdy.10163. PMID: 12412020. Dyer MA, Livesey FJ, Cepko CL, Oliver G. Prox1 function controls progenitor cell proliferation and horizontal cell genesis in the mammalian retina. Nat Genet. 2003 May;34(1):53-8. doi: 10.1038/ng1144. PMID: 12692551. Lee S, Kang J, Yoo J, Ganesan SK, Cook SC, Aguilar B, Ramu S, Lee J, Hong YK. Prox1 physically and functionally interacts with COUP-TFII to specify lymphatic endothelial cell fate. Blood. 2009 Feb 19;113(8):1856-9. doi: 10.1182/blood-2008-03-145789. Epub 2008 Sep 24. PMID: 18815287; PMCID: PMC2647678. Elsir T, Smits A, Lindström MS, Nistér M. Transcription factor PROX1: its role in development and cancer. Cancer Metastasis Rev. 2012 Dec;31(3-4):793-805. doi: 10.1007/s10555-012-9390-8. PMID: 22733308. Zhu L, Tian Q, Gao H, Wu K, Wang B, Ge G, Jiang S, Wang K, Zhou C, He J, Liu P, Ren Y, Wang B. PROX1 promotes breast cancer invasion and metastasis through WNT/β-catenin pathway via interacting with hnRNPK. Int J Biol Sci. 2022 Feb 28;18(5):2032-2046. doi: 10.7150/ijbs.68960. PMID: 35342346; PMCID: PMC8935233. Miettinen M, Wang ZF. Prox1 transcription factor as a marker for vascular tumors-evaluation of 314 vascular endothelial and 1086 nonvascular tumors. Am J Surg Pathol. 2012 Mar;36(3):351-9. doi: 10.1097/PAS.0b013e318236c312. PMID: 22067331; PMCID: PMC3288441. Rudzińska M, Mikula M, Arczewska KD, Gajda E, Sabalińska S, Stępień T, Ostrowski J, Czarnocka B. Transcription Factor Prospero Homeobox 1 (PROX1) as a Potential Angiogenic Regulator of Follicular Thyroid Cancer Dissemination. Int J Mol Sci. 2019 Nov 10;20(22):5619. doi: 10.3390/ijms20225619. PMID: 31717665; PMCID: PMC6888435. Park YL, Myung E, Park SY, Kim N, Oak CY, Myung DS, Cho SB, Lee WS, Kweon SS, Kim HS, Joo YE. Impact of prospero homeobox-1 on tumor cell behavior and prognosis in colorectal cancer. Am J Cancer Res. 2015 Oct 15;5(11):3286-300. PMID: 26807311; PMCID: PMC4697677. Michail A, Gkikas D, Stellas D, Kaltezioti V, Politis PK. Prox1 Suppresses the Proliferation of Breast Cancer Cells via Direct Inhibition of c-Myc Gene Expression. Cells. 2023 Jul 17;12(14):1869. doi: 10.3390/cells12141869. PMID: 37508533; PMCID: PMC10377922. Ntikoudi E, Pergaris A, Kykalos S, Politi E, Theocharis S. The Role of PROX1 in Neoplasia: A Key Player Often Overlooked. Diagnostics (Basel). 2022 Jul 4;12(7):1624. doi: 10.3390/diagnostics12071624. PMID: 35885529; PMCID: PMC9320018. Jernman J, Kallio P, Hagström J, Välimäki MJ, Haapasalo H, Alitalo K, Arola J, Haglund C. PROX1 is involved in progression of rectal neuroendocrine tumors, NETs. Virchows Arch. 2015 Sep;467(3):279-84. doi: 10.1007/s00428-015-1795-7. Epub 2015 Jun 11. PMID: 26063416. Liu Y, Zhang JB, Qin Y, Wang W, Wei L, Teng Y, Guo L, Zhang B, Lin Z, Liu J, Ren ZG, Ye QH, Xie Y. PROX1 promotes hepatocellular carcinoma metastasis by way of up-regulating hypoxia-inducible factor 1α expression and protein stability. Hepatology. 2013 Aug;58(2):692-705. doi: 10.1002/hep.26398. PMID: 23505027. Shimoda M, Takahashi M, Yoshimoto T, Kono T, Ikai I, Kubo H. A homeobox protein, prox1, is involved in the differentiation, proliferation, and prognosis in hepatocellular carcinoma. Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6005-11. doi: 10.1158/1078-0432.CCR-06-0712. PMID: 17062673. Liu Y, Ye X, Zhang JB, Ouyang H, Shen Z, Wu Y, Wang W, Wu J, Tao S, Yang X, Qiao K, Zhang J, Liu J, Fu Q, Xie Y. PROX1 promotes hepatocellular carcinoma proliferation and sorafenib resistance by enhancing β-catenin expression and nuclear translocation. Oncogene. 2015 Oct 29;34(44):5524-35. doi: 10.1038/onc.2015.7. Epub 2015 Feb 16. PMID: 25684142. Kwon S, Ban K, Hong YK, Sung JS, Choi I. PROX1, a Key Mediator of the Anti-Proliferative Effect of Rapamycin on Hepatocellular Carcinoma Cells. Cells. 2022 Jan 27;11(3):446. doi: 10.3390/cells11030446. PMID: 35159256; PMCID: PMC8834064. Chang TM, Hung WC. The homeobox transcription factor Prox1 inhibits proliferation of hepatocellular carcinoma cells by inducing p53-dependent senescence-like phenotype. Cancer Biol Ther. 2013 Mar;14(3):222-9. doi: 10.4161/cbt.23293. Epub 2013 Jan 4. PMID: 23291986; PMCID: PMC3595304. Kim YJ, Yoo JE, Jeon Y, Chong JU, Choi GH, Song DG, Jung SH, Oh BK, Park YN. Suppression of PROX1-mediated TERT expression in hepatitis B viral hepatocellular carcinoma. Int J Cancer. 2018 Dec 15;143(12):3155-3168. doi: 10.1002/ijc.31731. Epub 2018 Sep 27. PMID: 29987895. Dudas J, Mansuroglu T, Moriconi F, Haller F, Wilting J, Lorf T, Füzesi L, Ramadori G. Altered regulation of Prox1-gene-expression in liver tumors. BMC Cancer. 2008 Apr 9;8:92. doi: 10.1186/1471-2407-8-92. PMID: 18400094; PMCID: PMC2359759. Jo A, Denduluri S, Zhang B, Wang Z, Yin L, Yan Z, Kang R, Shi LL, Mok J, Lee MJ, Haydon RC. The versatile functions of Sox9 in development, stem cells, and human diseases. Genes Dis. 2014 Dec;1(2):149-161. doi: 10.1016/j.gendis.2014.09.004. PMID: 25685828; PMCID: PMC4326072. Symon A, Harley V. SOX9: A genomic view of tissue specific expression and action. Int J Biochem Cell Biol. 2017 Jun;87:18-22. doi: 10.1016/j.biocel.2017.03.005. Epub 2017 Mar 16. PMID: 28323209. Richtig G, Aigelsreiter A, Schwarzenbacher D, Ress AL, Adiprasito JB, Stiegelbauer V, Hoefler G, Schauer S, Kiesslich T, Kornprat P, Winder T, Eisner F, Gerger A, Stoeger H, Stauber R, Lackner C, Pichler M. SOX9 is a proliferation and stem cell factor in hepatocellular carcinoma and possess widespread prognostic significance in different cancer types. PLoS One. 2017 Nov 9;12(11):e0187814. doi: 10.1371/journal.pone.0187814. PMID: 29121666; PMCID: PMC5679634. Aguilar-Medina M, Avendaño-Félix M, Lizárraga-Verdugo E, Bermúdez M, Romero-Quintana JG, Ramos-Payan R, Ruíz-García E, López-Camarillo C. SOX9 Stem-Cell Factor: Clinical and Functional Relevance in Cancer. J Oncol. 2019 Apr 1;2019:6754040. doi: 10.1155/2019/6754040. PMID: 31057614; PMCID: PMC6463569. Gracz AD, Ramalingam S, Magness ST. Sox9 expression marks a subset of CD24-expressing small intestine epithelial stem cells that form organoids in vitro. Am J Physiol Gastrointest Liver Physiol. 2010 May;298(5):G590-600. doi: 10.1152/ajpgi.00470.2009. Epub 2010 Feb 25. PMID: 20185687; PMCID: PMC2867430. Scott CE, Wynn SL, Sesay A, Cruz C, Cheung M, Gomez Gaviro MV, Booth S, Gao B, Cheah KS, Lovell-Badge R, Briscoe J. SOX9 induces and maintains neural stem cells. Nat Neurosci. 2010 Oct;13(10):1181-9. doi: 10.1038/nn.2646. PMID: 20871603. Fabra-Beser J, Alves Medeiros de Araujo J, Marques-Coelho D, Goff LA, Costa MR, Müller U, Gil-Sanz C. Differential Expression Levels of Sox9 in Early Neocortical Radial Glial Cells Regulate the Decision between Stem Cell Maintenance and Differentiation. J Neurosci. 2021 Aug 18;41(33):6969-6986. doi: 10.1523/JNEUROSCI.2905-20.2021. Epub 2021 Jul 15. PMID: 34266896; PMCID: PMC8372026. Panda M, Tripathi SK, Biswal BK. SOX9: An emerging driving factor from cancer progression to drug resistance. Biochim Biophys Acta Rev Cancer. 2021 Apr;1875(2):188517. doi: 10.1016/j.bbcan.2021.188517. Epub 2021 Jan 29. PMID: 33524528. Aldaz P, Otaegi-Ugartemendia M, Saenz-Antoñanzas A, Garcia-Puga M, Moreno-Valladares M, Flores JM, Gerovska D, Arauzo-Bravo MJ, Samprón N, Matheu A, Carrasco-Garcia E. SOX9 promotes tumor progression through the axis BMI1-p21 CIP . Sci Rep. 2020 Jan 15;10(1):357. doi: 10.1038/s41598-019-57047-w. PMID: 31941916; PMCID: PMC6962164. Wehrli BM, Huang W, De Crombrugghe B, Ayala AG, Czerniak B. Sox9, a master regulator of chondrogenesis, distinguishes mesenchymal chondrosarcoma from other small blue round cell tumors. Hum Pathol. 2003 Mar;34(3):263-9. doi: 10.1053/hupa.2003.41. PMID: 12673561. Sardar D, Chen HC, Reyes A, Varadharajan S, Jain A, Mohila C, Curry R, Lozzi B, Rajendran K, Cervantes A, Yu K, Jalali A, Rao G, Mack SC, Deneen B. Sox9 directs divergent epigenomic states in brain tumor subtypes. Proc Natl Acad Sci U S A. 2022 Jul 19;119(29):e2202015119. doi: 10.1073/pnas.2202015119. Epub 2022 Jul 15. PMID: 35858326; PMCID: PMC9303974. Zhong H, Lu W, Tang Y, Wiel C, Wei Y, Cao J, Riedlinger G, Papagiannakopoulos T, Guo JY, Bergo MO, Kang Y, Ganesan S, Sabaawy HE, Pine SR. SOX9 drives KRAS-induced lung adenocarcinoma progression and suppresses anti-tumor immunity. Oncogene. 2023 Jun;42(27):2183-2194. doi: 10.1038/s41388-023-02715-5. Epub 2023 May 31. PMID: 37258742. Yuan X, Huang L, Luo W, Zhao Y, Nashan B, Yu F, Liu Y. Diagnostic and Prognostic Significances of SOX9 in Thymic Epithelial Tumor. Front Oncol. 2021 Oct 28;11:708735. doi: 10.3389/fonc.2021.708735. PMID: 34778027; PMCID: PMC8580949. Ma Y, Shepherd J, Zhao D, Bollu LR, Tahaney WM, Hill J, Zhang Y, Mazumdar A, Brown PH. SOX9 Is Essential for Triple-Negative Breast Cancer Cell Survival and Metastasis. Mol Cancer Res. 2020 Dec;18(12):1825-1838. doi: 10.1158/1541-7786.MCR-19-0311. Epub 2020 Jul 13. PMID: 32661114; PMCID: PMC7718423. Ruzinova MB, Ma C, Brunt EM, Goss CW, Vachharajani N, Chapman WC, Liu TC. SOX9 Expression Is Superior to Other Stem Cell Markers K19 and EpCAM in Predicting Prognosis in Hepatocellular Carcinoma. Am J Surg Pathol. 2023 Jan 1;47(1):1-11. doi: 10.1097/PAS.0000000000001990. Epub 2022 Nov 3. PMID: 36322988. Guo C, Zhou S, Yi W, Yang P, Li O, Liu J, Peng C. SOX9/MKLN1-AS Axis Induces Hepatocellular Carcinoma Proliferation and Epithelial-Mesenchymal Transition. Biochem Genet. 2022 Dec;60(6):1914-1933. doi: 10.1007/s10528-022-10196-6. Epub 2022 Feb 9. PMID: 35138470. Ren Z, Chen Y, Shi L, Shao F, Sun Y, Ge J, Zhang J, Zang Y. Sox9/CXCL5 axis facilitates tumour cell growth and invasion in hepatocellular carcinoma. FEBS J. 2022 Jun;289(12):3535-3549. doi: 10.1111/febs.16357. Epub 2022 Jan 25. PMID: 35038357. Liu C, Liu L, Chen X, Cheng J, Zhang H, Shen J, Shan J, Xu Y, Yang Z, Lai M, Qian C. Sox9 regulates self-renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma. Hepatology. 2016 Jul;64(1):117-29. doi: 10.1002/hep.28509. Epub 2016 Mar 25. PMID: 26910875. Kawai T, Yasuchika K, Ishii T, Miyauchi Y, Kojima H, Yamaoka R, Katayama H, Yoshitoshi EY, Ogiso S, Kita S, Yasuda K, Fukumitsu K, Komori J, Hatano E, Kawaguchi Y, Uemoto S. SOX9 is a novel cancer stem cell marker surrogated by osteopontin in human hepatocellular carcinoma. Sci Rep. 2016 Jul 26;6:30489. doi: 10.1038/srep30489. PMID: 27457505; PMCID: PMC4960550. Liu Y, Zhuo S, Zhou Y, Ma L, Sun Z, Wu X, Wang XW, Gao B, Yang Y. Yap-Sox9 signaling determines hepatocyte plasticity and lineage-specific hepatocarcinogenesis. J Hepatol. 2022 Mar;76(3):652-664. doi: 10.1016/j.jhep.2021.11.010. Epub 2021 Nov 15. PMID: 34793870; PMCID: PMC8858854. Li B, Liu D, Yang P, Li HY, Wang D. miR-613 inhibits liver cancer stem cell expansion by regulating SOX9 pathway. Gene. 2019 Jul 30;707:78-85. doi: 10.1016/j.gene.2019.05.015. Epub 2019 May 7. PMID: 31075412. Pierfelice TJ, Schreck KC, Eberhart CG, Gaiano N. Notch, neural stem cells, and brain tumors. Cold Spring Harb Symp Quant Biol. 2008;73:367-75. doi: 10.1101/sqb.2008.73.013. Epub 2008 Nov 6. PMID: 19022772; PMCID: PMC4510468. Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res. 2004;6(6):R605-15. doi: 10.1186/bcr920. Epub 2004 Aug 16. PMID: 15535842; PMCID: PMC1064073. Hori K, Sen A, Artavanis-Tsakonas S. Notch signaling at a glance. J Cell Sci. 2013 May 15;126(Pt 10):2135-40. doi: 10.1242/jcs.127308. Epub 2013 May 31. PMID: 23729744; PMCID: PMC3672934. Gaiano N, Fishell G. The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci. 2002;25:471-90. doi: 10.1146/annurev.neuro.25.030702.130823. Epub 2002 Mar 25. PMID: 12052917. Fiúza UM, Arias AM. Cell and molecular biology of Notch. J Endocrinol. 2007 Sep;194(3):459-74. doi: 10.1677/JOE-07-0242. PMID: 17761886. D'Assoro AB, Leon-Ferre R, Braune EB, Lendahl U. Roles of Notch Signaling in the Tumor Microenvironment. Int J Mol Sci. 2022 Jun 2;23(11):6241. doi: 10.3390/ijms23116241. PMID: 35682918; PMCID: PMC9181414. Bigas A, D'Altri T, Espinosa L. The Notch pathway in hematopoietic stem cells. Curr Top Microbiol Immunol. 2012;360:1-18. doi: 10.1007/82_2012_229. PMID: 22692832. Nowell CS, Radtke F. Notch as a tumour suppressor. Nat Rev Cancer. 2017 Mar;17(3):145-159. doi: 10.1038/nrc.2016.145. Epub 2017 Feb 3. PMID: 28154375. Meurette O, Mehlen P. Notch Signaling in the Tumor Microenvironment. Cancer Cell. 2018 Oct 8;34(4):536-548. doi: 10.1016/j.ccell.2018.07.009. Epub 2018 Aug 23. PMID: 30146333. Capaccione KM, Pine SR. The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis. 2013 Jul;34(7):1420-30. doi: 10.1093/carcin/bgt127. Epub 2013 Apr 12. PMID: 23585460; PMCID: PMC3697894. Ferreira A, Aster JC. Notch signaling in cancer: Complexity and challenges on the path to clinical translation. Semin Cancer Biol. 2022 Oct;85:95-106. doi: 10.1016/j.semcancer.2021.04.008. Epub 2021 Apr 20. PMID: 33862222. Li X, Yan X, Wang Y, Kaur B, Han H, Yu J. The Notch signaling pathway: a potential target for cancer immunotherapy. J Hematol Oncol. 2023 May 2;16(1):45. doi: 10.1186/s13045-023-01439-z. PMID: 37131214; PMCID: PMC10155406. Aster JC, Pear WS, Blacklow SC. The Varied Roles of Notch in Cancer. Annu Rev Pathol. 2017 Jan 24;12:245-275. doi: 10.1146/annurev-pathol-052016-100127. Epub 2016 Dec 5. PMID: 27959635; PMCID: PMC5933931. Zhou B, Lin W, Long Y, Yang Y, Zhang H, Wu K, Chu Q. Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct Target Ther. 2022 Mar 24;7(1):95. doi: 10.1038/s41392-022-00934-y. PMID: 35332121; PMCID: PMC8948217. Hu YY, Zheng MH, Zhang R, Liang YM, Han H. Notch signaling pathway and cancer metastasis. Adv Exp Med Biol. 2012;727:186-98. doi: 10.1007/978-1-4614-0899-4_14. PMID: 22399348. Zhu C, Ho YJ, Salomao MA, Dapito DH, Bartolome A, Schwabe RF, Lee JS, Lowe SW, Pajvani UB. Notch activity characterizes a common hepatocellular carcinoma subtype with unique molecular and clinicopathologic features. J Hepatol. 2021 Mar;74(3):613-626. doi: 10.1016/j.jhep.2020.09.032. Epub 2020 Oct 8. PMID: 33038431; PMCID: PMC7897246. Villanueva A, Alsinet C, Yanger K, Hoshida Y, Zong Y, Toffanin S, Rodriguez-Carunchio L, Solé M, Thung S, Stanger BZ, Llovet JM. Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology. 2012 Dec;143(6):1660-1669.e7. doi: 10.1053/j.gastro.2012.09.002. Epub 2012 Sep 11. PMID: 22974708; PMCID: PMC3505826. Viatour P, Ehmer U, Saddic LA, Dorrell C, Andersen JB, Lin C, Zmoos AF, Mazur PK, Schaffer BE, Ostermeier A, Vogel H, Sylvester KG, Thorgeirsson SS, Grompe M, Sage J. Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J Exp Med. 2011 Sep 26;208(10):1963-76. doi: 10.1084/jem.20110198. Epub 2011 Aug 29. PMID: 21875955; PMCID: PMC3182062. Sun L, Sun G, Yu Y, Coy DH. Is Notch Signaling a Specific Target in Hepatocellular Carcinoma? Anticancer Agents Med Chem. 2015;15(7):809-15. doi: 10.2174/1871520615666150202102809. PMID: 25642981. Clotman F, Lannoy VJ, Reber M, Cereghini S, Cassiman D, Jacquemin P, Roskams T, Rousseau GG, Lemaigre FP. The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development. 2002 Apr;129(8):1819-28. doi: 10.1242/dev.129.8.1819. PMID: 11934848. Pierreux CE, Vanhorenbeeck V, Jacquemin P, Lemaigre FP, Rousseau GG. The transcription factor hepatocyte nuclear factor-6/Onecut-1 controls the expression of its paralog Onecut-3 in developing mouse endoderm. J Biol Chem. 2004 Dec 3;279(49):51298-304. doi: 10.1074/jbc.M409038200. Epub 2004 Sep 20. PMID: 15381696. Zhang H, Ables ET, Pope CF, Washington MK, Hipkens S, Means AL, Path G, Seufert J, Costa RH, Leiter AB, Magnuson MA, Gannon M. Multiple, temporal-specific roles for HNF6 in pancreatic endocrine and ductal differentiation. Mech Dev. 2009 Dec;126(11-12):958-73. doi: 10.1016/j.mod.2009.09.006. Epub 2009 Sep 18. PMID: 19766716; PMCID: PMC2783291. Landry C, Clotman F, Hioki T, Oda H, Picard JJ, Lemaigre FP, Rousseau GG. HNF-6 is expressed in endoderm derivatives and nervous system of the mouse embryo and participates to the cross-regulatory network of liver-enriched transcription factors. Dev Biol. 1997 Dec 15;192(2):247-57. doi: 10.1006/dbio.1997.8757. PMID: 9441665. Audouard E, Schakman O, Ginion A, Bertrand L, Gailly P, Clotman F. The Onecut transcription factor HNF-6 contributes to proper reorganization of Purkinje cells during postnatal cerebellum development. Mol Cell Neurosci. 2013 Sep;56:159-68. doi: 10.1016/j.mcn.2013.05.001. Epub 2013 May 10. PMID: 23669529. Jiang K, Jiao Y, Liu Y, Fu D, Geng H, Chen L, Chen H, Shen X, Sun L, Ding K. HNF6 promotes tumor growth in colorectal cancer and enhances liver metastasis in mouse model. J Cell Physiol. 2019 Apr;234(4):3675-3684. doi: 10.1002/jcp.27140. Epub 2018 Sep 7. PMID: 30256389. Lehner F, Kulik U, Klempnauer J, Borlak J. The hepatocyte nuclear factor 6 (HNF6) and FOXA2 are key regulators in colorectal liver metastases. FASEB J. 2007 May;21(7):1445-62. doi: 10.1096/fj.06-6575com. Epub 2007 Feb 5. PMID: 17283222. Yuan XW, Wang DM, Hu Y, Tang YN, Shi WW, Guo XJ, Song JG. Hepatocyte nuclear factor 6 suppresses the migration and invasive growth of lung cancer cells through p53 and the inhibition of epithelial-mesenchymal transition. J Biol Chem. 2013 Oct 25;288(43):31206-16. doi: 10.1074/jbc.M113.480285. Epub 2013 Sep 10. PMID: 24022481; PMCID: PMC3829431. Pekala KR, Ma X, Kropp PA, Petersen CP, Hudgens CW, Chung CH, Shi C, Merchant NB, Maitra A, Means AL, Gannon MA. Loss of HNF6 expression correlates with human pancreatic cancer progression. Lab Invest. 2014 May;94(5):517-27. doi: 10.1038/labinvest.2014.47. Epub 2014 Mar 17. PMID: 24638272; PMCID: PMC4068339. Yuan XW, Wang DM, Hu Y, Tang YN, Shi WW, Guo XJ, Song JG. Hepatocyte nuclear factor 6 suppresses the migration and invasive growth of lung cancer cells through p53 and the inhibition of epithelial-mesenchymal transition. J Biol Chem. 2013 Oct 25;288(43):31206-16. doi: 10.1074/jbc.M113.480285. Epub 2013 Sep 10. PMID: 24022481; PMCID: PMC3829431. Sun H, Tang H, Xie D, Jia Z, Ma Z, Wei D, Mishra L, Gao Y, Zheng S, Xie K, Peng Z. Krüppel-like Factor 4 Blocks Hepatocellular Carcinoma Dedifferentiation and Progression through Activation of Hepatocyte Nuclear Factor-6. Clin Cancer Res. 2016 Jan 15;22(2):502-12. doi: 10.1158/1078-0432.CCR-15-0528. Epub 2015 Sep 2. PMID: 26338995; PMCID: PMC4715982. Lehner F, Kulik U, Klempnauer J, Borlak J. Inhibition of the liver enriched protein FOXA2 recovers HNF6 activity in human colon carcinoma and liver hepatoma cells. PLoS One. 2010 Oct 13;5(10):e13344. doi: 10.1371/journal.pone.0013344. PMID: 20967225; PMCID: PMC2954183. Hayashi Y, Wang W, Ninomiya T, Nagano H, Ohta K, Itoh H. Liver enriched transcription factors and differentiation of hepatocellular carcinoma. Mol Pathol. 1999 Feb;52(1):19-24. doi: 10.1136/mp.52.1.19. PMID: 10439834; PMCID: PMC395665. Rausa F, Samadani U, Ye H, Lim L, Fletcher CF, Jenkins NA, Copeland NG, Costa RH. The cut-homeodomain transcriptional activator HNF-6 is coexpressed with its target gene HNF-3 beta in the developing murine liver and pancreas. Dev Biol. 1997 Dec 15;192(2):228-46. doi: 10.1006/dbio.1997.8744. PMID: 9441664. Kropp PA, Gannon M. Onecut transcription factors in development and disease. Trends Dev Biol. 2016;9:43-57. PMID: 28018056; PMCID: PMC5176019. Margagliotti S, Clotman F, Pierreux CE, Beaudry JB, Jacquemin P, Rousseau GG, Lemaigre FP. The Onecut transcription factors HNF-6/OC-1 and OC-2 regulate early liver expansion by controlling hepatoblast migration. Dev Biol. 2007 Nov 15;311(2):579-89. doi: 10.1016/j.ydbio.2007.09.013. Epub 2007 Sep 16. PMID: 17936262. Freeman MR, Rotinen M, You S. ONECUT2 as a new therapeutic target in androgen receptor-indifferent prostate cancer. Transl Cancer Res. 2019 Nov;8(7):2677-2679. doi: 10.21037/tcr.2019.10.15. PMID: 35117025; PMCID: PMC8798022. Kropp PA, Gannon M. Onecut transcription factors in development and disease. Trends Dev Biol. 2016;9:43-57. PMID: 28018056; PMCID: PMC5176019. Yu J, Li D, Jiang H. Emerging role of ONECUT2 in tumors. Oncol Lett. 2020 Dec;20(6):328. doi: 10.3892/ol.2020.12192. Epub 2020 Oct 6. PMID: 33101497; PMCID: PMC7577075. Kaochar S, Mitsiades N. Multimodal action of ONECUT2 in driving neuroendocrine prostate cancer. Transl Cancer Res. 2019 Mar;8(Suppl 2):S198-S203. doi: 10.21037/tcr.2019.02.08. PMID: 31360645; PMCID: PMC6662936. Rotinen M, You S, Yang J, Coetzee SG, Reis-Sobreiro M, Huang WC, Huang F, Pan X, Yáñez A, Hazelett DJ, Chu CY, Steadman K, Morrissey CM, Nelson PS, Corey E, Chung LWK, Freedland SJ, Di Vizio D, Garraway IP, Murali R, Knudsen BS, Freeman MR. ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis. Nat Med. 2018 Dec;24(12):1887-1898. doi: 10.1038/s41591-018-0241-1. Epub 2018 Nov 26. PMID: 30478421; PMCID: PMC6614557. Rotinen M, You S, Yang J, Coetzee SG, Reis-Sobreiro M, Huang WC, Huang F, Pan X, Yáñez A, Hazelett DJ, Chu CY, Steadman K, Morrissey CM, Nelson PS, Corey E, Chung LWK, Freedland SJ, Di Vizio D, Garraway IP, Murali R, Knudsen BS, Freeman MR. ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis. Nat Med. 2018 Dec;24(12):1887-1898. doi: 10.1038/s41591-018-0241-1. Epub 2018 Nov 26. PMID: 30478421; PMCID: PMC6614557. Liu D, Zhang T, Chen X, Zhang B, Wang Y, Xie M, Ji X, Sun M, Huang W, Xia L. ONECUT2 facilitates hepatocellular carcinoma metastasis by transcriptionally upregulating FGF2 and ACLY. Cell Death Dis. 2021 Nov 27;12(12):1113. doi: 10.1038/s41419-021-04410-3. Erratum in: Cell Death Dis. 2021 Dec 23;13(1):28. PMID: 34839358; PMCID: PMC8627506. Yu J, Li D, Jiang H. Emerging role of ONECUT2 in tumors. Oncol Lett. 2020 Dec;20(6):328. doi: 10.3892/ol.2020.12192. Epub 2020 Oct 6. PMID: 33101497; PMCID: PMC7577075. Holterman AX, Tan Y, Kim W, Yoo KW, Costa RH. Diminished hepatic expression of the HNF-6 transcription factor during bile duct obstruction. Hepatology. 2002 Jun;35(6):1392-9. doi: 10.1053/jhep.2002.33680. PMID: 12029624. Samadani U, Costa RH. The transcriptional activator hepatocyte nuclear factor 6 regulates liver gene expression. Mol Cell Biol. 1996 Nov;16(11):6273-84. doi: 10.1128/MCB.16.11.6273. PMID: 8887657; PMCID: PMC231630. Lau HH, Ng NHJ, Loo LSW, Jasmen JB, Teo AKK. The molecular functions of hepatocyte nuclear factors - In and beyond the liver. J Hepatol. 2018 May;68(5):1033-1048. doi: 10.1016/j.jhep.2017.11.026. Epub 2017 Nov 24. PMID: 29175243. Tafaleng EN, Mukherjee A, Bell A, Morita K, Guzman-Lepe J, Haep N, Florentino RM, Diaz-Aragon R, Frau C, Ostrowska A, Schultz JR, Martini PGV, Soto-Gutierrez A, Fox IJ. Hepatocyte Nuclear Factor 4 alpha 2 Messenger RNA Reprograms Liver-Enriched Transcription Factors and Functional Proteins in End-Stage Cirrhotic Human Hepatocytes. Hepatol Commun. 2021 Nov;5(11):1911-1926. doi: 10.1002/hep4.1763. Epub 2021 Jul 1. PMID: 34558820; PMCID: PMC8557308. Khan SF, Damerell V, Omar R, Du Toit M, Khan M, Maranyane HM, Mlaza M, Bleloch J, Bellis C, Sahm BDB, Peres J, ArulJothi KN, Prince S. The roles and regulation of TBX3 in development and disease. Gene. 2020 Feb 5;726:144223. doi: 10.1016/j.gene.2019.144223. Epub 2019 Oct 26. PMID: 31669645; PMCID: PMC7108957. Miao ZF, Liu XY, Xu HM, Wang ZN, Zhao TT, Song YX, Xing YN, Huang JY, Zhang JY, Xu H, Xu YY. Tbx3 overexpression in human gastric cancer is correlated with advanced tumor stage and nodal status and promotes cancer cell growth and invasion. Virchows Arch. 2016 Nov;469(5):505-513. doi: 10.1007/s00428-016-2007-9. Epub 2016 Aug 24. PMID: 27553355. Douglas NC, Papaioannou VE. The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia. 2013 Jun;18(2):143-7. doi: 10.1007/s10911-013-9282-8. Epub 2013 Apr 28. PMID: 23624936; PMCID: PMC3692603. Huang L, Shao W, Wang X, Li F, Mao W. TBX3 stimulates proliferation and stem cell self-renewal in bladder carcinoma. Histol Histopathol. 2023 Jan;38(1):65-72. doi: 10.14670/HH-18-496. Epub 2022 Jul 20. PMID: 35856500. Zhou J, Wu J, Wu G, Huang J, Zhang Y, Che J, Zhu K, Geng J, Fan Q. TBX18 knockdown sensitizes esophageal squamous cell carcinoma to radiotherapy by blocking the CHN1/RhoA axis. Radiother Oncol. 2023 Sep;186:109788. doi: 10.1016/j.radonc.2023.109788. Epub 2023 Jul 1. PMID: 37399907. Takeichi M, Nimura K, Mori M, Nakagami H, Kaneda Y. The transcription factors Tbx18 and Wt1 control the epicardial epithelial-mesenchymal transition through bi-directional regulation of Slug in murine primary epicardial cells. PLoS One. 2013;8(2):e57829. doi: 10.1371/journal.pone.0057829. Epub 2013 Feb 28. PMID: 23469079; PMCID: PMC3585213. Bolt CC, Negi S, Guimarães-Camboa N, Zhang H, Troy JM, Lu X, Kispert A, Evans SM, Stubbs L. Tbx18 Regulates the Differentiation of Periductal Smooth Muscle Stroma and the Maintenance of Epithelial Integrity in the Prostate. PLoS One. 2016 Apr 27;11(4):e0154413. doi: 10.1371/journal.pone.0154413. Erratum in: PLoS One. 2016;11(6):e0157283. PMID: 27120339; PMCID: PMC4847854. Gorabi AM, Hajighasemi S, Tafti HA, Atashi A, Soleimani M, Aghdami N, Saeid AK, Khori V, Panahi Y, Sahebkar A. TBX18 transcription factor overexpression in human-induced pluripotent stem cells increases their differentiation into pacemaker-like cells. J Cell Physiol. 2019 Feb;234(2):1534-1546. doi: 10.1002/jcp.27018. Epub 2018 Aug 5. PMID: 30078203. Ji X, Chen X, Zhang B, Xie M, Zhang T, Luo X, Liu D, Feng Y, Wang Y, Sun M, Li C, Huang W, Xia L. T-box transcription factor 19 promotes hepatocellular carcinoma metastasis through upregulating EGFR and RAC1. Oncogene. 2022 Apr;41(15):2225-2238. doi: 10.1038/s41388-022-02249-2. Epub 2022 Feb 26. PMID: 35217793. Li Z, Wang Y, Duan S, Shi Y, Li S, Zhang X, Ren J. Expression of TBX3 in Hepatocellular Carcinoma and Its Clinical Implication. Med Sci Monit. 2018 Dec 22;24:9324-9333. doi: 10.12659/MSM.909378. PMID: 30578408; PMCID: PMC6320639. Suresh D, Srinivas AN, Prashant A, Harikumar KB, Kumar DP. Therapeutic options in hepatocellular carcinoma: a comprehensive review. Clin Exp Med. 2023 Oct;23(6):1901-1916. doi: 10.1007/s10238-023-01014-3. Epub 2023 Feb 13. PMID: 36780119. Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, Zhou Z, Shu G, Yin G. Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022 Jan 3;7(1):3. doi: 10.1038/s41392-021-00762-6. PMID: 34980884; PMCID: PMC8724284. Clevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006 Nov 3;127(3):469-80. doi: 10.1016/j.cell.2006.10.018. PMID: 17081971. Steinhart Z, Angers S. Wnt signaling in development and tissue homeostasis. Development. 2018 Jun 8;145(11):dev146589. doi: 10.1242/dev.146589. PMID: 29884654. Perugorria MJ, Olaizola P, Labiano I, Esparza-Baquer A, Marzioni M, Marin JJG, Bujanda L, Banales JM. Wnt-β-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol. 2019 Feb;16(2):121-136. doi: 10.1038/s41575-018-0075-9. PMID: 30451972. He S, Tang S. WNT/β-catenin signaling in the development of liver cancers. Biomed Pharmacother. 2020 Dec;132:110851. doi: 10.1016/j.biopha.2020.110851. Epub 2020 Oct 17. PMID: 33080466. Yu F, Yu C, Li F, Zuo Y, Wang Y, Yao L, Wu C, Wang C, Ye L. Wnt/β-catenin signaling in cancers and targeted therapies. Signal Transduct Target Ther. 2021 Aug 30;6(1):307. doi: 10.1038/s41392-021-00701-5. PMID: 34456337; PMCID: PMC8403677. Zhang Y, Wang X. Targeting the Wnt/β-catenin signaling pathway in cancer. J Hematol Oncol. 2020 Dec 4;13(1):165. doi: 10.1186/s13045-020-00990-3. PMID: 33276800; PMCID: PMC7716495. Chatterjee A, Paul S, Bisht B, Bhattacharya S, Sivasubramaniam S, Paul MK. Advances in targeting the WNT/β-catenin signaling pathway in cancer. Drug Discov Today. 2022 Jan;27(1):82-101. doi: 10.1016/j.drudis.2021.07.007. Epub 2021 Jul 10. PMID: 34252612. Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017 Mar;36(11):1461-1473. doi: 10.1038/onc.2016.304. Epub 2016 Sep 12. PMID: 27617575; PMCID: PMC5357762. Deldar Abad Paskeh M, Mirzaei S, Ashrafizadeh M, Zarrabi A, Sethi G. Wnt/β-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways. J Hepatocell Carcinoma. 2021 Nov 25;8:1415-1444. doi: 10.2147/JHC.S336858. PMID: 34858888; PMCID: PMC8630469. Xu C, Xu Z, Zhang Y, Evert M, Calvisi DF, Chen X. β-Catenin signaling in hepatocellular carcinoma. J Clin Invest. 2022 Feb 15;132(4):e154515. doi: 10.1172/JCI154515. PMID: 35166233; PMCID: PMC8843739. Khalaf AM, Fuentes D, Morshid AI, Burke MR, Kaseb AO, Hassan M, Hazle JD, Elsayes KM. Role of Wnt/β-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance. J Hepatocell Carcinoma. 2018 Jun 27;5:61-73. doi: 10.2147/JHC.S156701. PMID: 29984212; PMCID: PMC6027703. Wang H, Shi X. SAC3D1 activates Wnt/β‑catenin signalling in hepatocellular carcinoma. Mol Med Rep. 2022 Oct;26(4):317. doi: 10.3892/mmr.2022.12833. Epub 2022 Aug 25. PMID: 36004462. Aoki T, Nishida N, Kudo M. Clinical Significance of the Duality of Wnt/β-Catenin Signaling in Human Hepatocellular Carcinoma. Cancers (Basel). 2022 Jan 17;14(2):444. doi: 10.3390/cancers14020444. PMID: 35053606; PMCID: PMC8773595. Ghedini GC, Ronca R, Presta M, Giacomini A. Future applications of FGF/FGFR inhibitors in cancer. Expert Rev Anticancer Ther. 2018 Sep;18(9):861-872. doi: 10.1080/14737140.2018.1491795. Epub 2018 Jul 2. PMID: 29936878. Ray AT, Mazot P, Brewer JR, Catela C, Dinsmore CJ, Soriano P. FGF signaling regulates development by processes beyond canonical pathways. Genes Dev. 2020 Dec 1;34(23-24):1735-1752. doi: 10.1101/gad.342956.120. Epub 2020 Nov 12. Erratum in: Genes Dev. 2021 May 1;35(9-10):783. PMID: 33184218; PMCID: PMC7706708. Teven CM, Farina EM, Rivas J, Reid RR. Fibroblast growth factor (FGF) signaling in development and skeletal diseases. Genes Dis. 2014 Dec 1;1(2):199-213. doi: 10.1016/j.gendis.2014.09.005. PMID: 25679016; PMCID: PMC4323088. Leerberg DM, Hopton RE, Draper BW. Fibroblast Growth Factor Receptors Function Redundantly During Zebrafish Embryonic Development. Genetics. 2019 Aug;212(4):1301-1319. doi: 10.1534/genetics.119.302345. Epub 2019 Jun 7. PMID: 31175226; PMCID: PMC6707458. Ornitz DM, Marie PJ. Fibroblast growth factor signaling in skeletal development and disease. Genes Dev. 2015 Jul 15;29(14):1463-86. doi: 10.1101/gad.266551.115. PMID: 26220993; PMCID: PMC4526732. Korc M, Friesel RE. The role of fibroblast growth factors in tumor growth. Curr Cancer Drug Targets. 2009 Aug;9(5):639-51. doi: 10.2174/156800909789057006. Epub 2009 Aug 1. PMID: 19508171; PMCID: PMC3664927. Loda A, Turati M, Semeraro F, Rezzola S, Ronca R. Exploring the FGF/FGFR System in Ocular Tumors: New Insights and Perspectives. Int J Mol Sci. 2022 Mar 30;23(7):3835. doi: 10.3390/ijms23073835. PMID: 35409195; PMCID: PMC8998873. Presta M, Chiodelli P, Giacomini A, Rusnati M, Ronca R. Fibroblast growth factors (FGFs) in cancer: FGF traps as a new therapeutic approach. Pharmacol Ther. 2017 Nov;179:171-187. doi: 10.1016/j.pharmthera.2017.05.013. Epub 2017 May 28. PMID: 28564583. Kumar V, Goutam RS, Park S, Lee U, Kim J. Functional Roles of FGF Signaling in Early Development of Vertebrate Embryos. Cells. 2021 Aug 20;10(8):2148. doi: 10.3390/cells10082148. PMID: 34440915; PMCID: PMC8391977. Wang Y, Liu D, Zhang T, Xia L. FGF/FGFR Signaling in Hepatocellular Carcinoma: From Carcinogenesis to Recent Therapeutic Intervention. Cancers (Basel). 2021 Mar 17;13(6):1360. doi: 10.3390/cancers13061360. PMID: 33802841; PMCID: PMC8002748. Chen Z, Jiang L, Liang L, Koral K, Zhang Q, Zhao L, Lu S, Tao J. The Role of Fibroblast Growth Factor 19 in Hepatocellular Carcinoma. Am J Pathol. 2021 Jul;191(7):1180-1192. doi: 10.1016/j.ajpath.2021.04.014. Epub 2021 May 14. PMID: 34000282; PMCID: PMC8351122. Wang Y, Liu D, Zhang T, Xia L. FGF/FGFR Signaling in Hepatocellular Carcinoma: From Carcinogenesis to Recent Therapeutic Intervention. Cancers (Basel). 2021 Mar 17;13(6):1360. doi: 10.3390/cancers13061360. PMID: 33802841; PMCID: PMC8002748. Motoo Y, Sawabu N, Nakanuma Y. Expression of epidermal growth factor and fibroblast growth factor in human hepatocellular carcinoma: an immunohistochemical study. Liver. 1991 Oct;11(5):272-7. doi: 10.1111/j.1600-0676.1991.tb00529.x. PMID: 1660093. Wang H, Yang J, Zhang K, Liu J, Li Y, Su W, Song N. Advances of Fibroblast Growth Factor/Receptor Signaling Pathway in Hepatocellular Carcinoma and its Pharmacotherapeutic Targets. Front Pharmacol. 2021 Apr 15;12:650388. doi: 10.3389/fphar.2021.650388. PMID: 33935756; PMCID: PMC8082422. Birchmeier C, Gherardi E. Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. Trends Cell Biol. 1998 Oct;8(10):404-10. doi: 10.1016/s0962-8924(98)01359-2. PMID: 9789329. Nakamura T, Mizuno S. The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine. Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(6):588-610. doi: 10.2183/pjab.86.588. PMID: 20551596; PMCID: PMC3081175. Sweeney WE Jr, Avner ED. The role of hepatocyte growth factor (HGF) at progressive stages of metanephric development. In Vitro Cell Dev Biol Anim. 1998 Feb;34(2):189-94. doi: 10.1007/s11626-998-0104-z. PMID: 9542659. Qi Y, Li M, Xu L, Chang Z, Shu X, Zhou L. Therapeutic role of human hepatocyte growth factor (HGF) in treating hair loss. PeerJ. 2016 Nov 1;4:e2624. doi: 10.7717/peerj.2624. PMID: 27833804; PMCID: PMC5101615. Nakamura T, Sakai K, Nakamura T, Matsumoto K. Hepatocyte growth factor twenty years on: Much more than a growth factor. J Gastroenterol Hepatol. 2011 Jan;26 Suppl 1:188-202. doi: 10.1111/j.1440-1746.2010.06549.x. PMID: 21199531. Mulcahy EQX, Colόn RR, Abounader R. HGF/MET Signaling in Malignant Brain Tumors. Int J Mol Sci. 2020 Oct 13;21(20):7546. doi: 10.3390/ijms21207546. PMID: 33066121; PMCID: PMC7590206. Modica C, Olivero M, Zuppini F, Milan M, Basilico C, Vigna E. HGF/MET Axis Induces Tumor Secretion of Tenascin-C and Promotes Stromal Rewiring in Pancreatic Cancer. Cancers (Basel). 2021 Jul 14;13(14):3519. doi: 10.3390/cancers13143519. PMID: 34298732; PMCID: PMC8305254. Matsumoto K, Umitsu M, De Silva DM, Roy A, Bottaro DP. Hepatocyte growth factor/MET in cancer progression and biomarker discovery. Cancer Sci. 2017 Mar;108(3):296-307. doi: 10.1111/cas.13156. PMID: 28064454; PMCID: PMC5378267. Pai P, Kittur SK. Hepatocyte growth factor: A novel tumor marker for breast cancer. J Cancer Res Ther. 2023 Apr;19(Supplement):S0. doi: 10.4103/jcrt.JCRT_1084_16. PMID: 37147943. Ding X, Xi W, Ji J, Cai Q, Jiang J, Shi M, Yu Y, Zhu Z, Zhang J. HGF derived from cancer‑associated fibroblasts promotes vascularization in gastric cancer via PI3K/AKT and ERK1/2 signaling. Oncol Rep. 2018 Aug;40(2):1185-1195. doi: 10.3892/or.2018.6500. Epub 2018 Jun 18. PMID: 29917165. Meng W, Chen T. Association between the HGF/c‑MET signaling pathway and tumorigenesis, progression and prognosis of hepatocellular carcinoma (Review). Oncol Rep. 2021 Sep;46(3):191. doi: 10.3892/or.2021.8142. Epub 2021 Jul 19. PMID: 34278495. Zhang T, Wang Y, Xie M, Ji X, Luo X, Chen X, Zhang B, Liu D, Feng Y, Sun M, Huang W, Xia L. HGF-mediated elevation of ETV1 facilitates hepatocellular carcinoma metastasis through upregulating PTK2 and c-MET. J Exp Clin Cancer Res. 2022 Sep 16;41(1):275. doi: 10.1186/s13046-022-02475-2. PMID: 36109787; PMCID: PMC9479266. Venepalli NK, Goff L. Targeting the HGF-cMET Axis in Hepatocellular Carcinoma. Int J Hepatol. 2013;2013:341636. doi: 10.1155/2013/341636. Epub 2013 Mar 31. PMID: 23606971; PMCID: PMC3626399. Wu MY, Hill CS. Tgf-beta superfamily signaling in embryonic development and homeostasis. Dev Cell. 2009 Mar;16(3):329-43. doi: 10.1016/j.devcel.2009.02.012. PMID: 19289080. Kitisin K, Saha T, Blake T, Golestaneh N, Deng M, Kim C, Tang Y, Shetty K, Mishra B, Mishra L. Tgf-Beta signaling in development. Sci STKE. 2007 Aug 14;2007(399):cm1. doi: 10.1126/stke.3992007cm1. PMID: 17699101. Lee JH, Massagué J. TGF-β in developmental and fibrogenic EMTs. Semin Cancer Biol. 2022 Nov;86(Pt 2):136-145. doi: 10.1016/j.semcancer.2022.09.004. Epub 2022 Sep 29. PMID: 36183999; PMCID: PMC10155902. Jia S, Meng A. TGFβ family signaling and development. Development. 2021 Mar 12;148(5):dev188490. doi: 10.1242/dev.188490. PMID: 33712443. Massagué J. TGF-β signaling in development and disease. FEBS Lett. 2012 Jul 4;586(14):1833. doi: 10.1016/j.febslet.2012.05.030. Epub 2012 May 28. PMID: 22651913. Syed V. TGF-β Signaling in Cancer. J Cell Biochem. 2016 Jun;117(6):1279-87. doi: 10.1002/jcb.25496. Epub 2016 Feb 11. PMID: 26774024. Sabbadini F, Bertolini M, De Matteis S, Mangiameli D, Contarelli S, Pietrobono S, Melisi D. The Multifaceted Role of TGF-β in Gastrointestinal Tumors. Cancers (Basel). 2021 Aug 5;13(16):3960. doi: 10.3390/cancers13163960. PMID: 34439114; PMCID: PMC8391793. Kuburich NA, Sabapathy T, Demestichas BR, Maddela JJ, den Hollander P, Mani SA. Proactive and reactive roles of TGF-β in cancer. Semin Cancer Biol. 2023 Oct;95:120-139. doi: 10.1016/j.semcancer.2023.08.002. Epub 2023 Aug 11. PMID: 37572731; PMCID: PMC10530624. MaruYama T, Chen W, Shibata H. TGF-β and Cancer Immunotherapy. Biol Pharm Bull. 2022;45(2):155-161. doi: 10.1248/bpb.b21-00966. PMID: 35110501. Chen J, Gingold JA, Su X. Immunomodulatory TGF-β Signaling in Hepatocellular Carcinoma. Trends Mol Med. 2019 Nov;25(11):1010-1023. doi: 10.1016/j.molmed.2019.06.007. Epub 2019 Jul 25. PMID: 31353124. Zaidi S, Gough NR, Mishra L. Mechanisms and clinical significance of TGF-β in hepatocellular cancer progression. Adv Cancer Res. 2022;156:227-248. doi: 10.1016/bs.acr.2022.02.002. Epub 2022 Mar 16. PMID: 35961701. Dituri F, Mancarella S, Cigliano A, Chieti A, Giannelli G. TGF-β as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives. Semin Liver Dis. 2019 Feb;39(1):53-69. doi: 10.1055/s-0038-1676121. Epub 2018 Dec 26. PMID: 30586675. Arrese M, Hernandez A, Astete L, Estrada L, Cabello-Verrugio C, Cabrera D. TGF-β and Hepatocellular Carcinoma: When A Friend Becomes An Enemy. Curr Protein Pept Sci. 2018;19(12):1172-1179. doi: 10.2174/1389203718666171117112619. PMID: 29150921. Shen Y, Wei Y, Wang Z, Jing Y, He H, Yuan J, Li R, Zhao Q, Wei L, Yang T, Lu J. TGF-β regulates hepatocellular carcinoma progression by inducing Treg cell polarization. Cell Physiol Biochem. 2015;35(4):1623-32. doi: 10.1159/000373976. Epub 2015 Mar 18. PMID: 25824460. Zhong Z, Jiao Z, Yu FX. The Hippo signaling pathway in development and regeneration. Cell Rep. 2024 Mar 7;43(3):113926. doi: 10.1016/j.celrep.2024.113926. Epub ahead of print. PMID: 38457338. Zheng Y, Pan D. The Hippo Signaling Pathway in Development and Disease. Dev Cell. 2019 Aug 5;50(3):264-282. doi: 10.1016/j.devcel.2019.06.003. PMID: 31386861; PMCID: PMC6748048. Pan D. The hippo signaling pathway in development and cancer. Dev Cell. 2010 Oct 19;19(4):491-505. doi: 10.1016/j.devcel.2010.09.011. PMID: 20951342; PMCID: PMC3124840. Masliantsev K, Karayan-Tapon L, Guichet PO. Hippo Signaling Pathway in Gliomas. Cells. 2021 Jan 18;10(1):184. doi: 10.3390/cells10010184. PMID: 33477668; PMCID: PMC7831924. Yang D, Zhang N, Li M, Hong T, Meng W, Ouyang T. The Hippo Signaling Pathway: The Trader of Tumor Microenvironment. Front Oncol. 2021 Nov 11;11:772134. doi: 10.3389/fonc.2021.772134. PMID: 34858852; PMCID: PMC8632547. Xiao Y, Dong J. The Hippo Signaling Pathway in Cancer: A Cell Cycle Perspective. Cancers (Basel). 2021 Dec 10;13(24):6214. doi: 10.3390/cancers13246214. PMID: 34944834; PMCID: PMC8699626. Li HL, Li QY, Jin MJ, Lu CF, Mu ZY, Xu WY, Song J, Zhang Y, Zhang SY. A review: hippo signaling pathway promotes tumor invasion and metastasis by regulating target gene expression. J Cancer Res Clin Oncol. 2021 Jun;147(6):1569-1585. doi: 10.1007/s00432-021-03604-8. Epub 2021 Apr 17. PMID: 33864521. Liu Y, Wang X, Yang Y. Hepatic Hippo signaling inhibits development of hepatocellular carcinoma. Clin Mol Hepatol. 2020 Oct;26(4):742-750. doi: 10.3350/cmh.2020.0178. Epub 2020 Sep 28. PMID: 32981290; PMCID: PMC7641559. Ma J, Huang X. Research progress in role of Hippo signaling pathway in diagnosis and treatment for hepatocellular carcinoma. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2021 Jun 28;46(6):637-643. English, Chinese. doi: 10.11817/j.issn.1672-7347.2021.200243. PMID: 34275933; PMCID: PMC10930194. Chang YS, Chou YP, Chung CC, Lee YT, Yen JC, Jeng LB, Chang JG. Molecular Classification of Hepatocellular Carcinoma Using Wnt-Hippo Signaling Pathway-Related Genes. Cancers (Basel). 2022 Sep 21;14(19):4580. doi: 10.3390/cancers14194580. PMID: 36230503; PMCID: PMC9559216. Zheng T, Wang J, Jiang H, Liu L. Hippo signaling in oval cells and hepatocarcinogenesis. Cancer Lett. 2011 Mar 28;302(2):91-9. doi: 10.1016/j.canlet.2010.12.008. Epub 2011 Jan 17. PMID: 21247686. Shi X, Zhu HR, Liu TT, Shen XZ, Zhu JM. The Hippo pathway in hepatocellular carcinoma: Non-coding RNAs in action. Cancer Lett. 2017 Aug 1;400:175-182. doi: 10.1016/j.canlet.2017.04.032. Epub 2017 Apr 29. PMID: 28461246. Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4360926","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":298135566,"identity":"1f61d612-f3f3-4b13-977b-9b744b4cb144","order_by":0,"name":"Ovais Shafi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIiWNgGAWjYDCCA2BSAow+JFQA2czMDURrYZyRcAakhZEoLQwQLYxtIBYBLXy3DzA+5qmxsJef3fyw4eG82mj+dqCWHxXbcGqRPJfAbMxzTCJxw51jhg2J247nzjjM2MDYc+Y2Ti0GZxjYJGewSSQYSCSYP0jcdiy3AaiFmbGNkJZ/EvbyM9I/NiTOOZY7nxgtEh/bJBgbbuQAHdZQk7uBkBbJM4zNBh/7gH65kVPYkHDsQO5GoJaD+PzCd4b54IOEb3Ugh21s/FFTlzvv/OGDD35U4NaCHguHweQBPOoxQB0pikfBKBgFo2CEAAC5U18ZCCVrXAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0003-0572-6129","institution":"Sindh Medical College - Jinnah Sindh Medical University / Dow University of Health Sciences, Karachi, Pakistan","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Ovais","middleName":"","lastName":"Shafi","suffix":""},{"id":298135567,"identity":"94aed133-c54a-4d03-8f62-2f68afa08e3e","order_by":1,"name":"Rahimeen Rajpar","email":"","orcid":"","institution":"Sindh Medical College - Jinnah Sindh Medical University / Dow University of Health Sciences, Karachi, Pakistan","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rahimeen","middleName":"","lastName":"Rajpar","suffix":""},{"id":298135568,"identity":"35f2b1a4-4967-4bd9-ab27-755fa4f2a25f","order_by":2,"name":"Shakaib Zafar","email":"","orcid":"","institution":"Aga Khan University Hospital, Pakistan","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shakaib","middleName":"","lastName":"Zafar","suffix":""},{"id":298135569,"identity":"ec0e15c5-0e3a-48b5-8624-15b8bc25e093","order_by":3,"name":"Saba Irfan","email":"","orcid":"","institution":"Michigan State University, USA","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Saba","middleName":"","lastName":"Irfan","suffix":""},{"id":298135570,"identity":"6b2d5f78-6543-4f6a-97c9-e06e652fecc8","order_by":4,"name":"Muhammad Ashar","email":"","orcid":"","institution":"Aga Khan University Hospital, Pakistan","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Muhammad","middleName":"","lastName":"Ashar","suffix":""},{"id":298135571,"identity":"17c3d39e-26f0-4d75-8c1c-e5812c41de4e","order_by":5,"name":"Shah Hussain Jafry","email":"","orcid":"","institution":"Sindh Medical College - Jinnah Sindh Medical University / Dow University of Health Sciences, Karachi, Pakistan","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shah","middleName":"Hussain","lastName":"Jafry","suffix":""},{"id":298135572,"identity":"06743f70-fb54-4cf2-8231-c0b881f5448f","order_by":6,"name":"Luqman Naseer Virk","email":"","orcid":"","institution":"Sindh Medical College - Jinnah Sindh Medical University / Dow University of Health Sciences, Karachi, Pakistan","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Luqman","middleName":"Naseer","lastName":"Virk","suffix":""},{"id":298135573,"identity":"3f516947-780a-425e-a469-5077a2bbf9eb","order_by":7,"name":"Raveena","email":"","orcid":"","institution":"Sindh Medical College - Jinnah Sindh Medical University / Dow University of Health Sciences, Karachi, Pakistan","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"","middleName":"","lastName":"Raveena","suffix":""}],"badges":[],"createdAt":"2024-05-02 20:30:04","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false,"coiExplicitlySet":false},"doi":"10.21203/rs.3.rs-4360926/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4360926/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":56024202,"identity":"5d9f9d88-dc84-461d-8338-a12f243be29c","added_by":"auto","created_at":"2024-05-07 16:47:09","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":220888,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA FLOW DIAGRAM:\u003c/strong\u003e This figure represents graphically the flow of citations in the study.\u003c/p\u003e","description":"","filename":"PRISMAFlowDiagram.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4360926/v1/fa3c0d810d0ce5fbf6c396d3.jpg"},{"id":56024925,"identity":"5ebdfc14-199c-418c-8f76-e5c6c5d7c0d7","added_by":"auto","created_at":"2024-05-07 16:55:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1881874,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4360926/v1/129db8b1-9ab1-4573-8e0f-9b7a704d165d.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eMapping Heterogeneity of Hepatocellular Carcinoma by Investigating Hepatocyte-Specific Genes/TFs/Pathways Across Cellular and Tumor Landscapes\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eHepatocellular carcinoma (HCC) is one of the most prevalent and lethal forms of cancer worldwide, representing a significant public health burden. Despite advances in treatment modalities, the prognosis for patients with HCC remains poor, largely due to tumor heterogeneity and therapeutic resistance [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. HCC tumors exhibit remarkable diversity in cellular phenotypes, molecular profiles, and therapeutic responses, posing significant challenges for effective clinical management. Understanding the molecular mechanisms driving the emergence of HCC heterogeneity and transdifferentiation is crucial for improving patient outcomes and developing targeted therapeutic strategies [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. A comprehensive investigation into the dysregulated expression of key transcription factors, signaling pathways, and developmental regulators implicated in HCC pathogenesis is essential for elucidating the complex molecular landscape of HCC tumors. Transcription factors such as HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, HNF6/Onecut1, and ONECUT2/HNF6β play critical roles in hepatocyte development and differentiation. Dysregulation of these transcription factors disrupts the genetic programming of hepatocytes, leading to the emergence of heterogeneous cell populations within HCC tumors. Additionally, signaling pathways such as the Wnt/β-catenin pathway, fibroblast growth factor (FGF) signaling, hepatocyte growth factor (HGF) signaling, transforming growth factor-beta (TGF-β) signaling, and the Hippo signaling pathway are frequently dysregulated in HCC. Activation or inhibition of these pathways influences cellular fate decisions, promotes stemness, and modulates interactions with the tumor microenvironment, contributing to the heterogeneity observed in HCC. By investigating the dysregulated expression of these key regulators and signaling pathways, we can gain valuable insights into the molecular mechanisms driving HCC heterogeneity and transdifferentiation [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHepatocellular carcinoma (HCC) is characterized by significant heterogeneity, both at the cellular and molecular levels, which poses challenges for effective diagnosis and treatment. This study aims to investigate the mechanisms underlying the emergence of heterogeneity and transdifferentiation in HCC, drawing upon recent findings from research in developmental biology, genetics, and tumor biology [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Key pathways and transcriptional factors implicated in HCC heterogeneity and transdifferentiation are discussed, along with their roles in normal hepatocyte development and other tumors. Insights into the dysregulation of these pathways and factors shed light on the cellular plasticity and phenotypic diversity observed in HCC. Understanding the molecular underpinnings of HCC heterogeneity is crucial for developing targeted therapeutic approaches that can effectively combat this deadly disease [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003ePUBMED database, MEDLINE database, Google Scholar and open access/ subscription-based journals were searched with no date restrictions for published articles. The following key genes/ transcription factors/ signaling pathways involved in the proliferation and differentiation of hepatocytes were investigated for their expression in other cell-types, presence or role in other tumors, and for dysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:\u003c/p\u003e \u003cp\u003eHNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6β, TBX3/18, Wnt/β-catenin pathway, FGF, HGF, TGF-β, Hippo signaling pathway.\u003c/p\u003e \u003cp\u003eThe primary objective of this study is to trace the emergence of heterogeneity in HCC. The ultimate goal is to provide valuable insights into the HCC heterogeneity that in future may lead to potential future therapeutic targets for improved clinical management of patients with HCC.\u003c/p\u003e \u003cp\u003eScreening of the literature was also done on this same basis and related data was extracted. Literature search began in August 2020 and ended in November 2023. An in-depth investigation was conducted during this duration based on the parameters of the study as defined above. During revision, further literature was searched and referenced until March 2024. The literature search and all sections of the manuscript were checked multiple times during the months of revision (December 2023 \u0026ndash; March 2024) to maintain the highest accuracy possible. The prime focus of the literature search was to screen the literature on the basis of eligibility criteria mentioned above. It employs PRISMA guidelines as a tool for the investigation. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Publications only in \u0026lsquo;English\u0026rsquo; were used and there was no limitation on date of publication. Data extraction was based on these eligibility criteria. Studies were systematically reviewed based on the criteria mentioned in the methods section. No unpublished study was used or included.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 3066 articles were identified using database searching, and 2952 were recorded after duplicates removal. 2626 were excluded after screening of title/abstract, 51 were finally excluded, and 5 articles were excluded during data extraction. Finally, 270 articles were included as references.\u003c/p\u003e\n\u003cp\u003eHepatocellular carcinoma (HCC), the most prevalent form of liver cancer, typically arises from hepatocytes, the primary liver cell type responsible for crucial functions such as metabolism, protein synthesis, and detoxification [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]. When hepatocytes undergo genetic mutations or other alterations triggering uncontrolled growth, they can progress into hepatocellular carcinoma. Moreover, HCC can originate from progenitor cells or stem cells within the liver. The cell type-specific genetic architecture for hepatocytes encompasses a specific amalgamation of genes, transcription factors, and signaling pathways that precisely regulate their development, differentiation, and function [\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eKey components integral to the developmental biology of hepatocytes include a range of genes such as HNF4A, HNF1A, FOXA1, FOXA2, CEBPA, GATA4, GATA6, PROX1, SOX9, NOTCH2, HNF6, Onecut1, Onecut2, TBX3, and TBX18, along with associated signaling pathways like the Notch, Wnt/\u0026beta;-catenin, FGF, HGF/c-Met, TGF-\u0026beta;, and Hippo pathways [\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e]. These elements interact synergistically, orchestrating the specification, differentiation, and maturation of hepatocytes throughout development. Together, they constitute a regulatory network governing hepatocyte fate and function, essential for ensuring proper liver development and homeostasis. Disruption of this genetic architecture can result in developmental abnormalities or liver pathologies, highlighting its critical role in maintaining liver health and function [\u003cspan class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\n\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\n\u003ch2\u003eTumor heterogeneity in hepatocellular carcinoma:\u003c/h2\u003e\n\u003cp\u003eHepatocellular carcinoma (HCC) presents considerable variability among patients concerning its etiology, molecular characteristics, and clinical outcomes. Despite progress in genomic profiling pinpointing molecular subtypes of HCC, the precise contributors to this heterogeneity remain incompletely understood [\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e]. Delving deeper into the genetic, epigenetic, and microenvironmental factors influencing HCC heterogeneity holds promise for enhancing patient stratification and tailoring personalized treatment approaches. Although certain genetic mutations like TP53 and CTNNB1 (\u0026beta;-catenin) alterations are prevalent in HCC, the disease also demonstrates significant molecular diversity. Various molecular subtypes of HCC have been delineated based on disparate gene expression patterns, activation of signaling pathways, and genomic changes. This diversity complicates the development of targeted therapies and individualized treatment strategies, necessitating a more comprehensive understanding of HCC's molecular landscape for improved therapeutic outcomes [\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eTumor heterogeneity within hepatocellular carcinoma (HCC) encompasses diverse cellular and molecular characteristics observed both within individual tumors and among tumors within the same patient or across different patients. This heterogeneity manifests at multiple levels, including genetic, epigenetic, transcriptional, phenotypic, and spatial domains, each holding significance in deciphering HCC biology, predicting treatment responses, and formulating personalized therapeutic interventions [\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e]. Genetic heterogeneity in HCC tumors is evident through various genetic alterations such as mutations, copy number variations, and chromosomal rearrangements. Intra-tumoral genetic heterogeneity arises from distinct genetic mutations in different regions within a single tumor, while inter-tumoral genetic heterogeneity manifests as unique genetic profiles across different tumors from the same patient or among different patients. Epigenetic heterogeneity, characterized by variations in DNA methylation, histone modifications, and chromatin remodeling, contributes to differences in gene expression patterns, cellular differentiation states, and responses to therapy within and between HCC tumors [\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e]. Transcriptional heterogeneity in HCC tumors is reflected in diverse gene expression profiles, indicative of variability in cellular phenotypes, functional states, and signaling pathway activities, potentially influenced by tumor cell populations, microenvironmental cues, and clonal evolution dynamics. Phenotypic heterogeneity within HCC tumors encompasses variations in cellular morphology, proliferation rates, and expression of cell surface or lineage-specific markers, potentially stemming from clonal evolution, interactions with the tumor microenvironment, or stochastic processes. Spatial heterogeneity is observed in HCC tumors with distinct cellular and molecular features observed in different tumor regions, such as the tumor center, invasive front, and tumor-stromal interface, impacting tumor growth patterns, metastatic potential, and responses to localized therapies. Despite posing challenges for HCC diagnosis, prognosis, and treatment, tumor heterogeneity offers avenues for more personalized and effective therapeutic strategies. Comprehensive characterization utilizing multi-omics approaches, single-cell analysis, and spatial profiling techniques is imperative for advancing our understanding of HCC heterogeneity and devising tailored therapeutic interventions for individual patients, potentially mitigating treatment resistance and disease recurrence [\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eDifferentiation plasticity/transdifferentiation in Tumor Heterogeneity:\u003c/h2\u003e\n\u003cp\u003e\"Differentiation plasticity\" and \"transdifferentiation\" are mechanisms through which cancer cells can alter their differentiation state or lineage identity, thereby acquiring characteristics of different cell types. These processes significantly contribute to tumor heterogeneity, which encompasses a multitude of cellular and molecular features observed within and among tumors. Intra-tumoral heterogeneity, occurring within a single tumor, manifests as cancer cells exhibiting varying degrees of differentiation plasticity and transdifferentiation [\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e]. This results in the coexistence of distinct cellular phenotypes within the tumor, resembling different stages of differentiation or even different cell lineages. For instance, some cancer cells may retain characteristics of the original tissue of origin, such as hepatocytes in hepatocellular carcinoma, while others undergo transdifferentiation into cell types resembling mesenchymal cells or other lineages, adding to the diverse cellular composition within tumors. Inter-tumoral heterogeneity, observed across different tumors, arises from variability in differentiation plasticity and transdifferentiation, leading to differences in cellular phenotypes and lineage identities. Even tumors originating from the same tissue of origin may display diverse differentiation states and lineage characteristics due to individual disparities in genetic background, environmental exposures, and microenvironmental influences [\u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e]. Clonal evolution further contributes to inter-tumoral heterogeneity, as subpopulations of cancer cells with distinct differentiation properties emerge and proliferate over time, amplifying tumor diversity. The presence of differentiation plasticity and transdifferentiation within tumors significantly impacts tumor behavior, aggressiveness, and response to therapy [\u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e]. Cells with different differentiation states may exhibit varying proliferative capacities, metastatic potential, and resistance to treatment. For example, cancer cells undergoing epithelial-to-mesenchymal transition (EMT) via transdifferentiation may acquire invasive properties and resistance to conventional therapies, fueling tumor progression and metastasis. The resulting heterogeneity poses challenges for cancer diagnosis, prognosis, and treatment, as therapies targeting specific cellular phenotypes or lineage markers may prove less effective against heterogeneous tumors [\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInvestigating Hepatocyte-specific Genes/Signaling Pathways/TFs to trace HCC Heterogeneity\u003c/strong\u003e:\u003c/p\u003e\n\u003c/div\u003e\n\u003ch2\u003e1. HNF4A\u003c/h2\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eExpression in Other Cell-Types:\u003c/h2\u003e\n\u003cp\u003eHNF4A (Hepatocyte Nuclear Factor 4 Alpha) serves as an important transcription factor crucial for the development and functionality of hepatocytes, overseeing the expression of genes critical for liver development, metabolism, and homeostasis. Despite its primary association with hepatocyte biology, HNF4A also manifests expression and functional significance in diverse cell types and tissues [\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e]. In the realm of intestinal epithelial cells, HNF4A's presence regulates cell differentiation and function, vital for maintaining the intestinal epithelial barrier and modulating nutrient absorption and metabolism. Deficiency in HNF4A within the intestine may result in developmental anomalies and compromised barrier integrity, impacting overall gastrointestinal health. In pancreatic \u0026beta;-cells, HNF4A holds indispensable roles in both developmental progression and functional integrity, orchestrating the expression of genes critical for \u0026beta;-cell differentiation, insulin secretion, and glucose metabolism [\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e]. Mutations in HNF4A are implicated in maturity-onset diabetes of the young type 1 (MODY1), characterized by insulin secretion defects stemming from \u0026beta;-cell dysfunction. Furthermore, within renal tubular cells of the kidney, HNF4A governs the expression of genes essential for renal development, electrolyte transport, and fluid balance, essential for ensuring proper renal tubular epithelial cell differentiation and function [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. Dysregulation of HNF4A is associated with renal cysts and renal dysfunction in clinical contexts. During embryonic development, HNF4A emerges as a critical player in the differentiation of intestinal and pancreatic progenitor cells, steering their trajectory towards mature hepatocytes, pancreatic \u0026beta;-cells, and intestinal epithelial cells. This regulatory function ensures proper organogenesis and functionality. Additionally, in adipocytes within adipose tissue, HNF4A's presence dictates adipocyte differentiation, lipid metabolism, and adipokine secretion, implicating its role in metabolic disorders and obesity when dysregulated [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e]. Collectively, HNF4A's widespread expression and multidimensional roles across various cell types underscore its significance in orchestrating diverse physiological processes throughout the body, transcending its conventional association solely with hepatocytes [\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003ePresence or Role in Other Tumors:\u003c/h2\u003e\n\u003cp\u003eThe influence of HNF4A (Hepatocyte Nuclear Factor 4 Alpha) on tumor pathogenesis extends beyond its conventional role in normal tissue development, encompassing various tumors where its presence or functions are discernible. In colorectal cancer (CRC), HNF4A's involvement in the development and homeostasis of intestinal epithelial cells is important [\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e]. Dysregulation of HNF4A expression or function has been implicated in CRC carcinogenesis, where reduced expression of HNF4A in CRC tumors compared to normal colon tissue is observed. Functioning as a tumor suppressor, HNF4A regulates genes governing cell proliferation, apoptosis, and differentiation, with loss of its function associated with tumor progression and adverse prognosis in CRC patients. Similarly, in pancreatic cancer, HNF4A plays a role in pancreatic development and \u0026beta;-cell differentiation, with dysregulation implicated in tumorigenesis [\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e]. Acting as a tumor suppressor, HNF4A governs genes involved in cell cycle control, epithelial-mesenchymal transition (EMT), and glucose metabolism. Reduced HNF4A expression correlates with increased tumor aggressiveness and diminished patient survival. In renal cell carcinoma (RCC), HNF4A's expression in renal tubular cells underscores its role in renal development and function. Dysregulation of HNF4A expression in RCC is linked to tumor progression and metastasis, with its tumor-suppressive functions mediated through genes controlling cell proliferation, apoptosis, and renal differentiation. In endometrial cancer, HNF4A's expression in the endometrium and its regulatory role in endometrial development and differentiation are significant [\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e]. Dysregulation of HNF4A expression in endometrial cancer is associated with tumor aggressiveness and poor prognosis, with its tumor-suppressive actions modulating genes significant for cell cycle regulation, hormone signaling, and epithelial integrity. Similarly, in prostate cancer, HNF4A's expression in the prostate gland impacts prostate development and differentiation [\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e]. Dysregulation of HNF4A expression in prostate cancer contributes to tumor progression and metastasis, with its tumor-suppressive functions mediated through genes controlling cell proliferation, differentiation, and androgen receptor signaling. Overall, HNF4A's contextual roles in diverse tumors underscore its significance as either a tumor suppressor or promoter, contingent upon cellular context and specific molecular pathways involved. Insights into HNF4A's role in tumor biology hold potential for developing novel therapeutic strategies in cancer treatment [\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003ch2\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:\u003c/h2\u003e\n\u003cp\u003eDysregulated expression of HNF4A in hepatocellular carcinoma (HCC) contributes significantly to the emergence of transdifferentiation and heterogeneity features through diverse mechanisms, drawing upon its roles in other cell types and tumors [\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e]. Primarily, HNF4A serves as a key transcription factor in maintaining the identity and function of hepatocytes. Its dysregulated expression in HCC can precipitate the downregulation or loss of hepatocyte-specific genes, disrupting the genetic programming of hepatocytes and resulting in a loss of their characteristic identity. This loss of differentiation state sets a cellular context conducive to transdifferentiation into other cell types, thereby fostering intra-tumoral heterogeneity [\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e]. Moreover, dysregulated HNF4A expression may activate alternative differentiation pathways or lineage-specifying transcription factors within HCC cells. For instance, HNF4A's regulatory roles in various cell types such as intestinal epithelial cells, pancreatic \u0026beta;-cells, or renal tubular cells may be invoked, leading to the activation of alternative differentiation programs. Consequently, HCC cells may transdifferentiate into cell types resembling these diverse lineages, further fueling heterogeneity. Furthermore, HNF4A normally maintains the stability and lineage commitment of hepatocytes, suppressing their plasticity and preventing lineage switching. However, dysregulated expression in HCC disrupts this regulatory function, fostering enhanced cellular plasticity and increasing the propensity for transdifferentiation. HCC cells with dysregulated HNF4A expression exhibit greater flexibility in adopting alternative cell fates, thereby contributing to intra-tumoral heterogeneity. Additionally, dysregulated HNF4A expression may perturb signaling pathways crucial for cell fate determination and differentiation, such as Wnt/\u0026beta;-catenin, Notch, or TGF-\u0026beta; pathways. Such alterations, as observed in pancreatic cancer, can promote epithelial-to-mesenchymal transition (EMT) or induce stemness programs, thereby facilitating transdifferentiation and fostering tumor heterogeneity within HCC. HNF4A's interactions with other transcription factors and co-regulators are disrupted by its dysregulated expression in HCC. This disruption can lead to aberrant activation or repression of downstream target genes, further contributing to the emergence of transdifferentiation and heterogeneity features within the tumor [\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e]. Dysregulated expression of HNF4A in HCC disrupts hepatocyte identity, activates alternative differentiation pathways, enhances cellular plasticity, alters signaling pathways, and perturbs the interplay with other transcription factors. These mechanisms collectively contribute to the emergence of transdifferentiation and heterogeneity features within the tumor, underscoring the importance of understanding these processes in elucidating HCC pathogenesis and devising targeted therapeutic strategies [\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003ch2\u003e2. HNF1A\u003c/h2\u003e\n\u003cdiv id=\"Sec11\" class=\"Section3\"\u003e\n\u003ch2\u003eExpression in Other Cell-Types:\u003c/h2\u003e\n\u003cp\u003eHNF1A (Hepatocyte Nuclear Factor 1 Alpha) is a transcription factor. It plays roles in hepatocyte development and function. However, its influence extends beyond hepatocytes, encompassing various other cell types and tissues [\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e]. In pancreatic \u0026beta;-cells, crucial for regulating blood glucose levels through insulin secretion, HNF1A orchestrates the expression of genes governing \u0026beta;-cell differentiation, insulin secretion, and glucose metabolism. Mutations in HNF1A are linked to maturity-onset diabetes of the young type 3 (MODY3), characterized by impaired insulin secretion owing to \u0026beta;-cell dysfunction. Similarly, HNF1A asserts its presence in intestinal epithelial cells, where it governs their differentiation and function, influencing nutrient absorption, epithelial barrier integrity, and mucosal immunity. Mutations in HNF1A have implications in intestinal disorders like inflammatory bowel disease (IBD) and colorectal cancer [\u003cspan class=\"CitationRef\"\u003e38\u003c/span\u003e]. Moreover, in renal tubular cells, HNF1A regulates genes important for renal development, electrolyte transport, and fluid balance, with mutations associated with renal cysts and dysfunction. In endometrial epithelial cells of the uterus, HNF1A's regulatory role extends to endometrial development, differentiation, and menstrual cycle regulation. Its involvement in endometrial disorders such as hyperplasia and cancer underscores its significance in uterine health [\u003cspan class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e]. Additionally, in gastric epithelial cells, HNF1A governs genes essential for gastric development, mucin production, and acid secretion. Its implications in gastric disorders like gastritis, ulcers, and cancer highlight its role in gastric health. HNF1A demonstrates widespread expression and diverse roles across multiple cell types and tissues beyond hepatocytes [\u003cspan class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e43\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n\u003ch2\u003ePresence or Role in Other Tumors:\u003c/h2\u003e\n\u003cp\u003eThe developmental influence of HNF1A (Hepatocyte Nuclear Factor 1 Alpha) transcends its conventional role, also shaping the pathogenesis of diverse tumors. In pancreatic cancer, HNF1A's involvement in pancreatic \u0026beta;-cell development and function is significant. Dysregulation of HNF1A expression or function is implicated in pancreatic cancer progression, where it acts as a tumor suppressor by governing genes critical for cell cycle control, differentiation, and glucose metabolism [\u003cspan class=\"CitationRef\"\u003e44\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e45\u003c/span\u003e]. Reduced HNF1A expression correlates with increased tumor aggressiveness and diminished patient survival. Similarly, in colorectal cancer (CRC), HNF1A's presence in the intestinal epithelium influences cell differentiation and function. Dysregulation of HNF1A expression is observed in CRC, where it may serve as a tumor suppressor by modulating genes involved in cell proliferation, apoptosis, and epithelial barrier integrity. Loss of HNF1A function correlates with tumor progression and metastasis in CRC. Moreover, in renal cell carcinoma (RCC), HNF1A's expression in renal tubular cells plays a crucial role in renal development and function. Dysregulation of HNF1A expression in RCC is linked to tumor aggressiveness and poor prognosis, with its tumor-suppressive functions mediated through genes controlling cell cycle control, epithelial differentiation, and renal homeostasis. In endometrial cancer, HNF1A's regulatory role in the endometrial epithelium extends to endometrial development and differentiation [\u003cspan class=\"CitationRef\"\u003e46\u003c/span\u003e]. Dysregulation of HNF1A expression contributes to tumor aggressiveness and poor prognosis in endometrial cancer, where it acts as a tumor suppressor by modulating genes involved in cell cycle regulation, hormone signaling, and epithelial integrity. Furthermore, in gastric cancer, HNF1A's expression in the gastric epithelium influences gastric development and function. Dysregulation of HNF1A expression in gastric cancer is associated with tumor progression and metastasis, with its tumor-suppressive actions modulating genes governing cell proliferation, differentiation, and gastric mucin production [\u003cspan class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e48\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n\u003ch2\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:\u003c/h2\u003e\n\u003cp\u003eDysregulated expression of HNF1A in hepatocellular carcinoma (HCC) can contribute to the emergence of transdifferentiation and heterogeneity features through various mechanisms, considering its roles in other cell types and tumors. HNF1A plays a critical role in maintaining the identity and function of hepatocytes by regulating the expression of hepatocyte-specific genes [\u003cspan class=\"CitationRef\"\u003e49\u003c/span\u003e]. Dysregulated expression of HNF1A in HCC may lead to the downregulation or loss of expression of hepatocyte-specific genes, disrupting the genetic programming of hepatocytes and causing a loss of hepatocyte identity. This loss of differentiation state may create a cellular context conducive to transdifferentiation into other cell types, contributing to heterogeneity within the tumor. Moreover, dysregulated HNF1A expression may activate alternative differentiation pathways or lineage-specifying transcription factors in HCC cells [\u003cspan class=\"CitationRef\"\u003e50\u003c/span\u003e]. For instance, in pancreatic \u0026beta;-cells, HNF1A regulates genes involved in insulin secretion and glucose metabolism. Dysregulation of HNF1A in HCC may lead to the activation of these alternative differentiation programs, driving transdifferentiation of HCC cells into cell types resembling pancreatic \u0026beta;-cells, intestinal epithelial cells, or other cell types where HNF1A plays a role. Furthermore, HNF1A is involved in maintaining the stability and lineage commitment of hepatocytes, suppressing their plasticity and preventing lineage switching. Dysregulated expression of HNF1A in HCC may disrupt this regulatory function, leading to enhanced cellular plasticity and an increased propensity for transdifferentiation [\u003cspan class=\"CitationRef\"\u003e51\u003c/span\u003e]. HCC cells with dysregulated HNF1A expression may exhibit greater flexibility in adopting alternative cell fates, such as acquiring features of pancreatic \u0026beta;-cells, intestinal epithelial cells, or other cell types where HNF1A is involved. Additionally, dysregulated HNF1A expression in HCC may affect signaling pathways involved in cell fate determination and differentiation. For instance, in colorectal cancer, HNF1A regulates genes involved in intestinal development and homeostasis. Dysregulation of HNF1A in HCC may lead to alterations in signaling pathways such as Wnt/\u0026beta;-catenin, Notch, or TGF-\u0026beta;, which promote epithelial-to-mesenchymal transition (EMT) or induce stemness programs, facilitating transdifferentiation and promoting heterogeneity within the tumor. Moreover, HNF1A interacts with other transcription factors and co-regulators to regulate gene expression networks involved in cell differentiation and function. Dysregulated expression of HNF1A in HCC may disrupt these interactions, leading to aberrant activation or repression of downstream target genes and contributing to the emergence of transdifferentiation and heterogeneity features [\u003cspan class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e53\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n\u003ch2\u003e3. FOXA1/2\u003c/h2\u003e\n\u003cdiv id=\"Sec15\" class=\"Section3\"\u003e\n\u003ch2\u003eExpression in Other Cell-Types:\u003c/h2\u003e\n\u003cp\u003eFOXA1 and FOXA2 (Forkhead Box A1 and A2) are transcription factors with roles extending beyond hepatocytes, encompassing essential functions in various cell types [\u003cspan class=\"CitationRef\"\u003e54\u003c/span\u003e]. In lung epithelial cells, FOXA1 and FOXA2 orchestrate lung development and maturation, regulating genes crucial for respiratory epithelial cell differentiation, surfactant production, and airway maintenance throughout lung development stages. In pancreatic \u0026beta;-cells, FOXA1 and FOXA2 contribute significantly to pancreatic development, particularly in insulin-producing \u0026beta;-cell differentiation and function. Their regulation of genes involved in pancreas organogenesis, glucose metabolism, and insulin secretion is integral, and disruptions in their expression can impede pancreatic development and disrupt glucose homeostasis. Similarly, in prostate epithelial cells, FOXA1 holds prominence, governing prostate gland morphogenesis, differentiation, and epithelial identity maintenance. Its regulatory role extends to genes pertinent to prostate-specific functions, such as prostate-specific antigen (PSA) expression, with dysregulation correlating with prostate cancer progression [\u003cspan class=\"CitationRef\"\u003e55\u003c/span\u003e]. In breast epithelial cells, FOXA1 assumes significance, influencing mammary gland development, and differentiation. Its modulation of genes associated with mammary gland morphogenesis, milk production, and hormone responsiveness is important, with FOXA1 expression linked to luminal epithelial cell fate and hormone receptor-positive breast cancer subtypes [\u003cspan class=\"CitationRef\"\u003e56\u003c/span\u003e]. Moreover, in endometrial epithelial cells, FOXA1 regulates genes important for endometrial development, differentiation, and response to hormonal cues. Its involvement in establishing endometrial receptivity for embryo implantation underscores its significance, while its implications in endometrial disorders, including endometrial cancer, highlight its multidimensional role. FOXA1 and FOXA2's broad expression and diverse functions across multiple cell types underscore their integral roles in coordinating various physiological processes throughout the body, beyond their conventional hepatocytic domain [\u003cspan class=\"CitationRef\"\u003e57\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e58\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n\u003ch2\u003ePresence or Role in Other Tumors:\u003c/h2\u003e\n\u003cp\u003eThe developmental significance of FOXA1 and FOXA2 transcends their conventional roles in tissue development, as they exert influence over the pathogenesis of diverse tumors [\u003cspan class=\"CitationRef\"\u003e59\u003c/span\u003e]. In prostate cancer, FOXA1 serves as a key transcription factor governing prostate development and differentiation. Dysregulated FOXA1 expression commonly characterizes prostate cancer, correlating with disease advancement and adverse prognosis. FOXA1 orchestrates genes integral to androgen receptor (AR) signaling, epithelial differentiation, and prostate-specific gene expression, thereby fostering tumor growth and survival [\u003cspan class=\"CitationRef\"\u003e60\u003c/span\u003e]. Moreover, FOXA1's association with the luminal subtype of prostate cancer underscores its role in hormone receptor-positive tumors. Similarly, in breast cancer, FOXA1's expression in luminal epithelial cells imparts crucial contributions to mammary gland development and hormone responsiveness. Altered FOXA1 expression accompanies breast cancer progression, particularly evident in hormone receptor-positive subtypes. FOXA1 regulates genes implicated in estrogen receptor (ER) signaling, luminal epithelial differentiation, and mammary gland morphogenesis, positively correlating with favorable prognoses in ER-positive breast cancer patients [\u003cspan class=\"CitationRef\"\u003e61\u003c/span\u003e]. In lung cancer, FOXA1 and FOXA2's involvement in lung development and their expression in lung epithelial cells tie them to tumorigenesis. Dysregulated expression potentially fuels lung cancer progression and metastasis by influencing epithelial differentiation and tumor cell plasticity, owing to their regulation of genes pertinent to lung maturation, surfactant production, and airway maintenance. In pancreatic cancer, FOXA1 and FOXA2's roles in pancreatic development and function position them as crucial players in tumorigenesis [\u003cspan class=\"CitationRef\"\u003e62\u003c/span\u003e]. Dysregulated expression is associated with tumor aggressiveness and poor prognosis, impacting pancreas organogenesis, insulin secretion, and glucose metabolism. Perturbations in expression may alter pancreatic progenitor cell differentiation, tumor cell survival, and metastatic propensity. Moreover, in endometrial cancer, FOXA1's involvement in endometrial development and hormone responsiveness implicates its role in pathogenesis. Dysregulated expression influences endometrial receptivity, hormone signaling, and epithelial differentiation, potentially driving tumor progression by modulating proliferation, hormone receptor expression, and response to hormonal therapy. In essence, dysregulated FOXA1 and FOXA2 expression in various tumors disrupts tissue development and homeostasis, fostering tumor progression and metastasis. Elucidating their roles in tumor biology holds promise for devising novel therapeutic strategies in cancer treatment [\u003cspan class=\"CitationRef\"\u003e63\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e64\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\n\u003ch2\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:\u003c/h2\u003e\n\u003cp\u003eDysregulated expression of FOXA1 and FOXA2 in hepatocellular carcinoma (HCC) can fuel the emergence of transdifferentiation and heterogeneity features through various mechanisms, considering their roles in other cell types and tumors [\u003cspan class=\"CitationRef\"\u003e65\u003c/span\u003e]. These mechanisms encompass loss of hepatocyte identity, activation of alternative differentiation pathways, enhanced cellular plasticity, altered signaling pathways, and interplay with other transcription factors. FOXA1 and FOXA2 play important roles in maintaining hepatocyte identity and function by regulating the expression of hepatocyte-specific genes. Dysregulated expression in HCC may lead to downregulation or loss of these genes, disrupting hepatocyte genetic programming and causing loss of hepatocyte identity. This loss of differentiation may foster a context conducive to transdifferentiation into other cell types, fostering intra-tumoral heterogeneity [\u003cspan class=\"CitationRef\"\u003e66\u003c/span\u003e]. Moreover, dysregulated FOXA1/2 expression may activate alternative differentiation pathways or lineage-specifying transcription factors in HCC cells. For instance, in lung epithelial cells, FOXA1/2 regulate genes involved in lung development. Dysregulation in HCC might activate these pathways, driving transdifferentiation into cell types resembling lung epithelial cells or other types where FOXA1/2 are active. Furthermore, FOXA1 and FOXA2 normally maintain cell identity and stability, suppressing cellular plasticity. Dysregulated expression may disrupt this function, increasing cellular plasticity and the propensity for transdifferentiation. HCC cells with altered FOXA1/2 expression may exhibit greater flexibility in adopting alternative cell fates [\u003cspan class=\"CitationRef\"\u003e67\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e69\u003c/span\u003e]. Altered FOXA1/2 expression in HCC may also affect signaling pathways involved in cell fate determination. For example, dysregulation could lead to changes in pathways like Wnt/\u0026beta;-catenin or Notch, promoting epithelial-to-mesenchymal transition or stemness programs, thus facilitating transdifferentiation and promoting heterogeneity [\u003cspan class=\"CitationRef\"\u003e70\u003c/span\u003e]. FOXA1 and FOXA2 interact with other transcription factors to regulate gene expression networks. Dysregulated expression in HCC may disrupt these interactions, leading to aberrant activation or repression of downstream target genes, thereby contributing to the emergence of transdifferentiation and heterogeneity features within the tumor [\u003cspan class=\"CitationRef\"\u003e71\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e72\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e73\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\n\u003ch2\u003e4. CEBPA\u003c/h2\u003e\n\u003cdiv id=\"Sec19\" class=\"Section3\"\u003e\n\u003ch2\u003eExpression in Other Cell-Types:\u003c/h2\u003e\n\u003cp\u003eCEBPA (CCAAT/enhancer-binding protein alpha) is a transcription factor recognized for its roles in the development and function of various cell types beyond hepatocytes. In myeloid cells, CEBPA holds a central position, governing their development and differentiation into granulocytes, monocytes, and dendritic cells. It orchestrates the expression of genes important for myeloid lineage commitment, maturation, and function, particularly promoting granulopoiesis and neutrophil differentiation [\u003cspan class=\"CitationRef\"\u003e74\u003c/span\u003e]. Moreover, in adipocytes, CEBPA emerges as a critical regulator of adipogenesis, steering precursor cells towards maturation into mature adipocytes. It exercises control over genes implicated in adipocyte differentiation, lipid metabolism, and adipokine secretion, thereby facilitating the formation of white adipose tissue and preserving metabolic equilibrium. In lung epithelial cells, CEBPA contributes to lung development and differentiation in the maturation of alveolar epithelial cells. It oversees the expression of genes vital for lung morphogenesis, surfactant production, and gas exchange, with its deficiency potentially resulting in compromised alveolar development and respiratory impairments [\u003cspan class=\"CitationRef\"\u003e75\u003c/span\u003e]. Similarly, in intestinal epithelial cells, CEBPA's involvement spans intestinal development, barrier function, and mucosal immunity. It plays a key role in steering intestinal stem cells towards differentiation into mature epithelial cell lineages like enterocytes and goblet cells. Dysregulation or deficiency of CEBPA in the intestine may disrupt epithelial homeostasis and escalate intestinal inflammation. Furthermore, in breast epithelial cells, CEBPA's influence is evident in mammary gland development and differentiation, particularly in the formation of luminal epithelial cells [\u003cspan class=\"CitationRef\"\u003e76\u003c/span\u003e]. It governs the expression of genes crucial for mammary gland morphogenesis, milk production, and hormone responsiveness, positioning itself as a marker of luminal epithelial cell fate and hormone receptor-positive breast cancer subtypes [\u003cspan class=\"CitationRef\"\u003e77\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\n\u003ch2\u003ePresence or Role in Other Tumors:\u003c/h2\u003e\n\u003cp\u003eThe developmental biology of CEBPA (CCAAT/enhancer-binding protein alpha) extends beyond its role in normal tissue development, as it also influences the pathogenesis of various tumors. CEBPA's presence or roles can be traced in other tumors: CEBPA is frequently mutated in Acute Myeloid Leukemia (AML), occurring in approximately 10\u0026ndash;15% of cases. Mutations can affect both the N-terminal transactivation domain and the C-terminal DNA-binding basic region, leading to loss of function or dominant-negative effects [\u003cspan class=\"CitationRef\"\u003e78\u003c/span\u003e]. Some AML cases exhibit CEBPA double mutations, altering transcriptional regulation and promoting myeloid progenitor proliferation. In liver cancer, particularly hepatocellular carcinoma (HCC), CEBPA's role is significant. While mutations in CEBPA are less common in HCC compared to AML, dysregulated expression can occur through various mechanisms, impacting hepatocyte differentiation and promoting tumor progression [\u003cspan class=\"CitationRef\"\u003e79\u003c/span\u003e]. CEBPA expression is associated with breast cancer progression and prognosis. Elevated expression in luminal-type tumors correlates with better outcomes, whereas downregulation in aggressive subtypes like triple-negative breast cancer contributes to tumor aggressiveness and therapy resistance. Dysregulation of CEBPA has been observed in lung cancer, particularly non-small cell lung carcinoma (NSCLC). Expression levels vary across NSCLC subtypes and disease stages, with increased expression linked to better prognosis in some cases and decreased expression associated with tumor progression and metastasis in others. In colorectal cancer (CRC), CEBPA expression levels fluctuate throughout tumor development stages, influencing cell proliferation, differentiation, and metastasis [\u003cspan class=\"CitationRef\"\u003e80\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e81\u003c/span\u003e]. However, the specific roles of CEBPA in CRC biology are yet to be fully understood.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\n\u003ch2\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:\u003c/h2\u003e\n\u003cp\u003eDysregulated expression of CEBPA (CCAAT/enhancer-binding protein alpha) in hepatocellular carcinoma (HCC) can contribute to the emergence of transdifferentiation and heterogeneity features through various mechanisms, considering its roles in other cell types and tumors. CEBPA is crucial for maintaining hepatocyte identity and function by regulating the expression of hepatocyte-specific genes [\u003cspan class=\"CitationRef\"\u003e82\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e83\u003c/span\u003e]. Dysregulated expression in HCC may disrupt the genetic programming of hepatocytes, leading to a loss of hepatocyte identity. Consequently, this loss of differentiation state may facilitate transdifferentiation into other cell types, contributing to tumor heterogeneity. Dysregulated CEBPA expression may activate alternative differentiation pathways or lineage-specifying transcription factors in HCC cells. For instance, in myeloid cells, CEBPA regulates genes involved in differentiation [\u003cspan class=\"CitationRef\"\u003e84\u003c/span\u003e]. This dysregulation in HCC may drive transdifferentiation into myeloid-like cells or other cell types where CEBPA plays a role. CEBPA is involved in maintaining cell identity and stability, suppressing cellular plasticity, and preventing lineage switching. Dysregulated expression in HCC may disrupt this regulatory function, leading to enhanced cellular plasticity. Consequently, HCC cells with dysregulated CEBPA expression may exhibit greater flexibility in adopting alternative cell fates. Dysregulated CEBPA expression in HCC may affect signaling pathways involved in cell fate determination and differentiation [\u003cspan class=\"CitationRef\"\u003e85\u003c/span\u003e]. Alterations in signaling pathways such as Wnt/\u0026beta;-catenin, Notch, or TGF-\u0026beta; may promote epithelial-to-mesenchymal transition (EMT) or induce stemness programs, facilitating transdifferentiation and promoting heterogeneity within the tumor. CEBPA interacts with other transcription factors and co-regulators to regulate gene expression networks involved in cell differentiation and function. Dysregulated expression in HCC may disrupt these interactions, leading to aberrant activation or repression of downstream target genes and contributing to the emergence of transdifferentiation and heterogeneity features [\u003cspan class=\"CitationRef\"\u003e86\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\n\u003ch2\u003e5. GATA4/6\u003c/h2\u003e\n\u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\n\u003ch2\u003eExpression in Other Cell-Types:\u003c/h2\u003e\n\u003cp\u003eGATA4 and GATA6 are transcription factors renowned for their roles in various developmental processes beyond hepatocytes. Their presence or roles can be traced in the development of numerous other cell types. In cardiomyocytes, GATA4 and GATA6 are crucial for heart development and function, regulating genes involved in cardiac lineage specification, cardiomyocyte proliferation, and cardiac morphogenesis [\u003cspan class=\"CitationRef\"\u003e87\u003c/span\u003e]. These transcription factors, expressed in cardiac progenitor cells, contribute to cardiogenesis and are associated with congenital heart defects and cardiomyopathies. Endodermal derivatives, such as the lungs, pancreas, and gastrointestinal tract, also rely on GATA4 and GATA6 for proper development. In the lung, these factors control genes necessary for lung branching morphogenesis, epithelial differentiation, and surfactant production. Similarly, in the pancreas, they oversee pancreatic progenitor cell fate and \u0026beta;-cell differentiation, while in the gastrointestinal tract, they regulate gut tube patterning, epithelial differentiation, and mucosal homeostasis [\u003cspan class=\"CitationRef\"\u003e88\u003c/span\u003e]. GATA4 and GATA6 play essential roles in ovarian granulosa cells, where they govern folliculogenesis and steroidogenesis by orchestrating granulosa cell proliferation, differentiation, and response to gonadotropin stimulation. Dysregulated expression in these cells can disrupt ovarian follicle development, potentially leading to infertility or ovarian dysfunction. Moreover, GATA4 and GATA6 are involved in adrenal cortex development and steroid hormone biosynthesis. They regulate genes important for adrenocortical cell fate determination, steroidogenic enzyme expression, and adrenal gland morphogenesis [\u003cspan class=\"CitationRef\"\u003e89\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e90\u003c/span\u003e]. Mutations in these transcription factors can result in adrenal insufficiency and congenital adrenal hyperplasia. In the testis, particularly in Sertoli cells, GATA4 plays a significant role in testicular development and spermatogenesis. It oversees genes responsible for Sertoli cell differentiation, germ cell support, and blood-testis barrier formation. Disruptions in GATA4 expression within Sertoli cells can impede testicular development and spermatogenesis, potentially leading to male infertility [\u003cspan class=\"CitationRef\"\u003e91\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e92\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\n\u003ch2\u003ePresence or Role in Other Tumors:\u003c/h2\u003e\n\u003cp\u003eThe developmental biology of GATA4 and GATA6 extends beyond normal tissue development, as these transcription factors are also implicated in the pathogenesis of various tumors. Here's how their presence or roles can be traced in other tumors. In cardiac tumors, particularly rare pediatric cardiac tumors like rhabdomyomas and teratomas, dysregulation of GATA4 and GATA6 has been observed [\u003cspan class=\"CitationRef\"\u003e93\u003c/span\u003e]. These tumors often exhibit abnormal expression patterns of these transcription factors, potentially contributing to their pathogenesis. However, further research is required to fully understand their role in cardiac tumor development [\u003cspan class=\"CitationRef\"\u003e94\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e95\u003c/span\u003e]. GATA4 and GATA6 are involved in gastric development and differentiation, and their dysregulation has been implicated in gastric cancer. Aberrant expression of these factors has been associated with gastric tumor progression, metastasis, and patient prognosis. They may modulate genes involved in gastric epithelial differentiation, proliferation, and invasion, thereby contributing to gastric cancer pathogenesis [\u003cspan class=\"CitationRef\"\u003e96\u003c/span\u003e]. In pancreatic cancer, GATA6 is frequently dysregulated, playing diverse roles in tumor progression and metastasis. Its upregulation in pancreatic ductal adenocarcinoma (PDAC) correlates with poor patient outcomes. GATA6 regulates genes involved in pancreatic development, epithelial-to-mesenchymal transition (EMT), and metastasis, fostering tumor aggressiveness and metastatic spread in pancreatic cancer. Ovarian cancer, particularly endometrioid and clear cell ovarian carcinomas, also exhibits dysregulation of GATA4 and GATA6. Their aberrant expression is associated with tumor progression, chemoresistance, and patient survival. These transcription factors may influence genes involved in ovarian epithelial differentiation, hormone signaling, and tumor cell proliferation, thus contributing to ovarian cancer pathogenesis [\u003cspan class=\"CitationRef\"\u003e97\u003c/span\u003e]. In colorectal cancer, dysregulation of GATA6 is observed, associated with tumor progression and metastasis. Elevated expression of GATA6 is detected in colorectal adenocarcinomas and correlates with poor patient prognosis. It regulates genes involved in intestinal epithelial differentiation, Wnt/\u0026beta;-catenin signaling, and epithelial-to-mesenchymal transition (EMT), thereby promoting colorectal cancer metastasis and invasion [\u003cspan class=\"CitationRef\"\u003e98\u003c/span\u003e].\u003c/p\u003e\n\u003cdiv id=\"Sec25\" class=\"Section3\"\u003e\n\u003ch2\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:\u003c/h2\u003e\n\u003cp\u003eGATA4 and GATA6 play essential roles in maintaining hepatocyte identity and function by regulating the expression of hepatocyte-specific genes. Dysregulated expression of these factors in HCC may lead to the downregulation or loss of expression of hepatocyte-specific genes, disrupting the genetic programming of hepatocytes and causing a loss of hepatocyte identity [\u003cspan class=\"CitationRef\"\u003e99\u003c/span\u003e]. This loss of differentiation state may create a cellular context conducive to transdifferentiation into other cell types, contributing to heterogeneity within the tumor. Dysregulated GATA4/6 expression may activate alternative differentiation pathways or lineage-specifying transcription factors in HCC cells. For example, in cardiac tumors, GATA4 and GATA6 dysregulation has been observed, indicating their potential to influence cardiac differentiation programs [\u003cspan class=\"CitationRef\"\u003e100\u003c/span\u003e]. Dysregulation of these factors in HCC may lead to the activation of these alternative differentiation programs, driving transdifferentiation of HCC cells into cardiac-like cells or other cell types where GATA4/6 play a role. GATA4 and GATA6 are involved in maintaining cell identity and stability, suppressing cellular plasticity, and preventing lineage switching. Dysregulated expression of these factors in HCC may disrupt this regulatory function, leading to enhanced cellular plasticity and increased propensity for transdifferentiation. HCC cells with dysregulated expression of GATA4/6 may exhibit greater flexibility in adopting alternative cell fates, such as acquiring features of cardiac cells, endodermal derivatives, or other cell types where GATA4/6 are involved [\u003cspan class=\"CitationRef\"\u003e101\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e102\u003c/span\u003e]. Dysregulated GATA4/6 expression in HCC may affect signaling pathways involved in cell fate determination and differentiation. For example, in pancreatic cancer, GATA6 dysregulation influences pancreatic differentiation and tumor progression. Dysregulation of these factors in HCC may lead to alterations in signaling pathways such as Wnt/\u0026beta;-catenin, Notch, or TGF-\u0026beta;, which promote epithelial-to-mesenchymal transition (EMT) or induce stemness programs, facilitating transdifferentiation and promoting heterogeneity within the tumor. GATA4 and GATA6 interact with other transcription factors and co-regulators to regulate gene expression networks involved in cell differentiation and function. Dysregulated expression of these factors in HCC may disrupt these interactions, leading to aberrant activation or repression of downstream target genes and contributing to the emergence of transdifferentiation and heterogeneity features [\u003cspan class=\"CitationRef\"\u003e103\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e104\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec26\" class=\"Section3\"\u003e\n\u003ch2\u003e6. PROX1\u003c/h2\u003e\n\u003cdiv id=\"Sec27\" class=\"Section4\"\u003e\n\u003ch2\u003eExpression in Other Cell-Types:\u003c/h2\u003e\n\u003cp\u003ePROX1 (Prospero homeobox protein 1) is a transcription factor with diverse roles in the development and function of various cell types beyond hepatocytes. Here's how its presence or roles can be traced in the development of other cell types. In lymphatic endothelial cells, PROX1 serves as a master regulator of lymphatic endothelial cell development and lymphangiogenesis [\u003cspan class=\"CitationRef\"\u003e105\u003c/span\u003e]. It is expressed in lymphatic endothelial progenitors and controls the expression of genes involved in lymphatic vessel specification, differentiation, and maintenance. Throughout life, PROX1 remains essential for the formation of the lymphatic vasculature, ensuring the regulation of lymphatic endothelial cell identity. Expressed in neural progenitor cells, PROX1 contributes to neural development and neurogenesis. It governs genes associated with neural progenitor cell proliferation, differentiation, and migration. Particularly vital for the central nervous system, PROX1 aids in the development of regions such as the cerebral cortex, hippocampus, and cerebellum, facilitating the establishment of neuronal circuits and synaptic connections. Within lens epithelial cells, PROX1 plays a crucial role in lens development and differentiation. It oversees genes necessary for lens fiber cell differentiation, lens morphogenesis, and maintaining lens transparency. Ensuring the perpetuation of lens epithelial cell identity and lens homeostasis is among the fundamental tasks carried out by PROX1 throughout an organism's life [\u003cspan class=\"CitationRef\"\u003e106\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e107\u003c/span\u003e]. In liver sinusoidal endothelial cells (LSECs), PROX1's expression is significant as it governs their development and function. By regulating genes involved in liver sinusoid formation, blood vessel integrity, and hepatic metabolism, PROX1 plays a vital role in maintaining the fenestrated phenotype of LSECs and promoting liver homeostasis. Within thyroid follicular cells, PROX1 participates in thyroid development and folliculogenesis. It regulates genes that contribute to thyroid follicle formation, thyroid hormone synthesis, and iodine metabolism. Essential for thyroid follicular cell differentiation and thyroid hormone production, PROX1's presence ensures proper functioning of the thyroid gland [\u003cspan class=\"CitationRef\"\u003e108\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e109\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e110\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec28\" class=\"Section2\"\u003e\n\u003ch2\u003ePresence or Role in Other Tumors:\u003c/h2\u003e\n\u003cp\u003eThe developmental biology of PROX1 (Prospero homeobox protein 1) extends beyond normal tissue development, as PROX1 dysregulation is implicated in the pathogenesis of various tumors. PROX1 is a master regulator of lymphatic endothelial cell development and lymphangiogenesis [\u003cspan class=\"CitationRef\"\u003e111\u003c/span\u003e]. Dysregulated PROX1 expression has been observed in lymphatic endothelial tumors such as lymphangiomas and lymphangiosarcomas. Aberrant expression of PROX1 may contribute to tumor angiogenesis, lymphatic vessel proliferation, and tumor metastasis by promoting lymphangiogenesis and lymphatic vessel invasion. PROX1 dysregulation has been implicated in hepatocellular carcinoma (HCC) [\u003cspan class=\"CitationRef\"\u003e112\u003c/span\u003e]. While PROX1 is normally expressed in hepatocytes and liver sinusoidal endothelial cells (LSECs), its expression is often downregulated or lost in HCC. Reduced PROX1 expression in HCC is associated with tumor progression, metastasis, and poor patient prognosis. PROX1 acts as a tumor suppressor in HCC by inhibiting tumor cell proliferation, inducing apoptosis, and suppressing angiogenesis. PROX1 dysregulation has been reported in thyroid cancer, particularly in papillary thyroid carcinoma (PTC) and anaplastic thyroid carcinoma (ATC). PROX1 expression is upregulated in thyroid cancer cells compared to normal thyroid tissue, and its expression levels correlate with tumor aggressiveness and patient prognosis. PROX1 promotes thyroid cancer cell proliferation, migration, and invasion by regulating genes involved in epithelial-mesenchymal transition (EMT), angiogenesis, and metastasis [\u003cspan class=\"CitationRef\"\u003e113\u003c/span\u003e]. PROX1 dysregulation has been associated with breast cancer progression and metastasis. In breast cancer, PROX1 expression is upregulated in invasive breast cancer subtypes compared to normal breast tissue, and its expression levels correlate with tumor grade, lymph node metastasis, and patient survival. PROX1 promotes breast cancer cell invasion and metastasis by regulating genes involved in EMT, extracellular matrix remodeling, and tumor cell dissemination. PROX1 dysregulation has been implicated in colon cancer progression and metastasis [\u003cspan class=\"CitationRef\"\u003e114\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e115\u003c/span\u003e]. In colon cancer, PROX1 expression is upregulated in invasive tumor tissues compared to normal colon epithelium, and its expression levels correlate with tumor stage and patient prognosis. PROX1 promotes colon cancer cell invasion and metastasis by regulating genes involved in EMT, cell motility, and tumor-stroma interactions [\u003cspan class=\"CitationRef\"\u003e116\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e117\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e118\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec29\" class=\"Section2\"\u003e\n\u003ch2\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:\u003c/h2\u003e\n\u003cp\u003ePROX1 is normally expressed in hepatocytes and liver sinusoidal endothelial cells (LSECs) and plays a role in maintaining hepatocyte identity and function. Dysregulated expression of PROX1 in HCC may lead to the downregulation or loss of hepatocyte-specific genes, disrupting the genetic programming of hepatocytes and causing a loss of hepatocyte identity [\u003cspan class=\"CitationRef\"\u003e119\u003c/span\u003e]. This loss of differentiation state may create a cellular context conducive to transdifferentiation into other cell types, contributing to heterogeneity within the tumor. Dysregulated PROX1 expression may activate alternative differentiation pathways or lineage-specifying transcription factors in HCC cells [\u003cspan class=\"CitationRef\"\u003e120\u003c/span\u003e]. For example, PROX1 is a master regulator of lymphatic endothelial cell development and lymphangiogenesis. Dysregulation of PROX1 in HCC may lead to the activation of these alternative differentiation programs, driving transdifferentiation of HCC cells into lymphatic endothelial-like cells or other cell types where PROX1 plays a role. PROX1 is involved in maintaining cell identity and stability, suppressing cellular plasticity, and preventing lineage switching [\u003cspan class=\"CitationRef\"\u003e121\u003c/span\u003e]. Dysregulated expression of PROX1 in HCC may disrupt this regulatory function, leading to enhanced cellular plasticity and increased propensity for transdifferentiation. HCC cells with dysregulated PROX1 expression may exhibit greater flexibility in adopting alternative cell fates, such as acquiring features of lymphatic endothelial cells, neural progenitor cells, or other cell types where PROX1 is involved. Dysregulated PROX1 expression in HCC may affect signaling pathways involved in cell fate determination and differentiation. For example, PROX1 dysregulation has been implicated in thyroid cancer progression, where it promotes tumor cell proliferation, migration, and invasion [\u003cspan class=\"CitationRef\"\u003e122\u003c/span\u003e]. Dysregulation of PROX1 in HCC may lead to alterations in signaling pathways such as Wnt/\u0026beta;-catenin, Notch, or TGF-\u0026beta;, which promote epithelial-to-mesenchymal transition (EMT) or induce stemness programs, facilitating transdifferentiation and promoting heterogeneity within the tumor. PROX1 interacts with other transcription factors and co-regulators to regulate gene expression networks involved in cell differentiation and function. Dysregulated expression of PROX1 in HCC may disrupt these interactions, leading to aberrant activation or repression of downstream target genes and contributing to the emergence of transdifferentiation and heterogeneity features [\u003cspan class=\"CitationRef\"\u003e123\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e124\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003ch2\u003e7. SOX9\u003c/h2\u003e\n\u003cdiv id=\"Sec31\" class=\"Section2\"\u003e\n\u003ch2\u003eExpression in Other Cell-Types:\u003c/h2\u003e\n\u003cp\u003eSOX9 is a transcription factor with diverse roles in the development and differentiation of various cell types beyond hepatocytes. Its presence or roles can be traced in the development of several other cell types. SOX9 is a master regulator of chondrogenesis, expressed in chondroprogenitor cells, where it plays a critical role in their differentiation into chondrocytes [\u003cspan class=\"CitationRef\"\u003e125\u003c/span\u003e]. Regulating the expression of genes essential for cartilage matrix synthesis, such as collagen type II and aggrecan, SOX9 is indispensable for cartilage development and skeletal morphogenesis. In the testis, SOX9 is expressed in Sertoli cells, contributing significantly to testicular development by regulating their differentiation and the formation of testicular cords. This transcription factor is crucial for male sex determination and the maintenance of testicular structure and function. In pancreatic development, SOX9 is involved in the differentiation of pancreatic progenitor cells into endocrine and exocrine cell lineages. It regulates genes crucial for pancreatic morphogenesis and is essential for the formation of pancreatic ducts and the differentiation of pancreatic progenitor cells into ductal epithelial cells [\u003cspan class=\"CitationRef\"\u003e126\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e127\u003c/span\u003e]. SOX9 also plays a role in hair follicle development and regeneration, expressed in hair follicle stem cells and regulating genes involved in stem cell maintenance, hair follicle morphogenesis, and hair cycling. It is vital for maintaining hair follicle stem cell populations and regenerating hair follicles during the hair growth cycle. Moreover, SOX9 is expressed in colonic epithelial cells, contributing to colonic development and homeostasis by regulating genes involved in epithelial differentiation, barrier function, and mucosal immunity [\u003cspan class=\"CitationRef\"\u003e128\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e129\u003c/span\u003e]. Essential for maintaining colonic epithelial integrity, SOX9 helps balance proliferation and differentiation of colonic epithelial cells [\u003cspan class=\"CitationRef\"\u003e130\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec32\" class=\"Section2\"\u003e\n\u003ch2\u003ePresence or Role in Other Tumors:\u003c/h2\u003e\n\u003cp\u003eSOX9 plays a significant role in various aspects of tumorigenesis and tumor progression across different types of cancers. Its involvement in other tumors can be observed as follows. In colorectal cancer (CRC), SOX9 is frequently upregulated and implicated in tumor initiation, progression, and metastasis [\u003cspan class=\"CitationRef\"\u003e131\u003c/span\u003e]. It regulates genes associated with epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cells, and metastatic spread. Elevated SOX9 expression in CRC correlates with poor prognosis and resistance to chemotherapy. Moreover, in pancreatic ductal adenocarcinoma (PDAC), SOX9 is overexpressed and linked to tumor aggressiveness and unfavorable patient outcomes. It governs genes involved in cancer cell proliferation, invasion, and metastasis. The expression of SOX9 in PDAC is associated with tumor grade, lymph node metastasis, and patient survival, suggesting its potential as both a prognostic marker and therapeutic target [\u003cspan class=\"CitationRef\"\u003e132\u003c/span\u003e]. In breast cancer, SOX9 expression correlates with disease progression and metastasis. It regulates genes implicated in cancer cell proliferation, migration, and invasion, and is involved in maintaining breast cancer stem cells. Elevated SOX9 levels in breast cancer are associated with poor prognosis and resistance to therapy. Similarly, SOX9 plays a critical role in prostate cancer initiation and progression by regulating genes involved in cancer cell proliferation, survival, and metastasis. Its expression is heightened in advanced prostate cancer, including castration-resistant prostate cancer (CRPC) and metastatic disease [\u003cspan class=\"CitationRef\"\u003e133\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e134\u003c/span\u003e]. Targeting SOX9 in prostate cancer could be a promising therapeutic approach to inhibit tumor growth and metastasis. Additionally, SOX9 is upregulated in glioblastoma, a highly aggressive brain tumor, where it contributes to tumor invasiveness and poor patient prognosis [\u003cspan class=\"CitationRef\"\u003e135\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e136\u003c/span\u003e]. It controls genes associated with glioblastoma cell migration, invasion, and angiogenesis. SOX9 expression in glioblastoma is linked to tumor recurrence and resistance to therapy, indicating its potential as a therapeutic target in this malignancy [\u003cspan class=\"CitationRef\"\u003e137\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e138\u003c/span\u003e].\u003c/p\u003e\n\u003cdiv id=\"Sec33\" class=\"Section3\"\u003e\n\u003ch2\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:\u003c/h2\u003e\n\u003cp\u003eSOX9, although not typically expressed in mature hepatocytes, can be upregulated in liver cancer, including hepatocellular carcinoma (HCC). This dysregulated expression of SOX9 may result in the downregulation or loss of hepatocyte-specific genes, disrupting the genetic programming essential for maintaining hepatocyte identity [\u003cspan class=\"CitationRef\"\u003e139\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e140\u003c/span\u003e]. Consequently, this loss of differentiation state within HCC cells may create an environment conducive to transdifferentiation into alternative cell types, thereby contributing to the heterogeneity observed within the tumor. Moreover, dysregulated SOX9 expression in HCC may trigger the activation of alternative differentiation pathways or lineage-specifying transcription factors. For instance, SOX9 is important in chondrogenesis and the development of various cell types like chondrocytes. Hence, its dysregulation in HCC could potentially activate chondrogenic differentiation programs, prompting the transdifferentiation of HCC cells into chondrocyte-like cells or other cell types where SOX9 exerts influence [\u003cspan class=\"CitationRef\"\u003e141\u003c/span\u003e]. SOX9's involvement in maintaining cellular plasticity and regulating cell fate decisions is well-documented. In the context of HCC, dysregulated expression of SOX9 may disrupt the normal cellular hierarchy and enhance cellular plasticity. This enhanced plasticity could enable HCC cells to adopt alternative cell fates, thereby facilitating their transdifferentiation into different cell types and contributing to the observed tumor heterogeneity. Furthermore, dysregulated SOX9 expression in HCC may impact various signaling pathways crucial for cell fate determination and differentiation. For example, SOX9 is implicated in the Wnt/\u0026beta;-catenin signaling pathway, which is frequently dysregulated in HCC [\u003cspan class=\"CitationRef\"\u003e142\u003c/span\u003e]. Such dysregulation of SOX9 might lead to aberrant activation of Wnt/\u0026beta;-catenin signaling, thereby promoting epithelial-to-mesenchymal transition (EMT) and facilitating the transdifferentiation of HCC cells into mesenchymal-like cells or other cell types. Additionally, SOX9's interactions with other transcription factors and co-regulators play an important role in regulating gene expression networks involved in cell differentiation and function. Dysregulated expression of SOX9 in HCC could disrupt these interactions, resulting in aberrant activation or repression of downstream target genes. This disruption may contribute to the emergence of transdifferentiation and heterogeneity features observed within HCC tumors [\u003cspan class=\"CitationRef\"\u003e143\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e144\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec34\" class=\"Section3\"\u003e\n\u003ch2\u003e8. Notch2\u003c/h2\u003e\n\u003cdiv id=\"Sec35\" class=\"Section4\"\u003e\n\u003ch2\u003eExpression in Other Cell-Types:\u003c/h2\u003e\n\u003cp\u003eNOTCH2, a signaling receptor, is involved in various cellular processes and developmental pathways across diverse tissues and organs. Its significance extends to the development of several cell types: In neural progenitor cells, NOTCH2 assumes a crucial role in neurogenesis and the establishment of the central nervous system. By orchestrating the delicate balance between neural stem cell self-renewal and differentiation, NOTCH2 governs the expression of genes important for neural fate specification [\u003cspan class=\"CitationRef\"\u003e145\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e146\u003c/span\u003e]. Consequently, NOTCH2 signaling is indispensable for maintaining the pool of neural progenitor cells and driving neuronal differentiation during the process of brain development [\u003cspan class=\"CitationRef\"\u003e147\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e148\u003c/span\u003e]. Furthermore, NOTCH2 signaling exerts profound effects on hematopoiesis and the differentiation of hematopoietic stem cells (HSCs) into diverse blood cell lineages. It regulates the balance between HSC self-renewal and differentiation into essential immune cell types such as T cells, B cells, and myeloid cells. By steering hematopoietic cell fate decisions, NOTCH2 signaling ensures the maintenance of immune cell homeostasis and effective immune responses [\u003cspan class=\"CitationRef\"\u003e149\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e150\u003c/span\u003e]. Moreover, in intestinal epithelial cells, NOTCH2 signaling plays a key role in governing the development and equilibrium of the intestinal epithelium. By regulating intestinal stem cell dynamics along the crypt-villus axis, NOTCH2 activation facilitates the differentiation of intestinal progenitors into functional absorptive enterocytes and secretory goblet cells. This orchestrated process contributes significantly to intestinal epithelial renewal and barrier integrity. In the context of skeletal development and bone remodeling, NOTCH2 signaling assumes significance in the differentiation of osteoblast precursor cells into mature osteoblasts, responsible for bone formation and mineralization [\u003cspan class=\"CitationRef\"\u003e151\u003c/span\u003e]. Additionally, NOTCH2 signaling influences the differentiation of osteoclast precursor cells into bone-resorbing osteoclasts, thereby contributing to the crucial balance of bone remodeling and homeostasis. In renal tubular epithelial cells, NOTCH2 signaling orchestrates kidney development and the maintenance of renal tubular epithelial cell function. By regulating the proliferation, differentiation, and polarization of renal tubular epithelial cells, NOTCH2 signaling contributes significantly to kidney morphogenesis and tubular integrity. However, dysregulated NOTCH2 signaling has been implicated in various kidney diseases, including polycystic kidney disease and renal fibrosis, underscoring its critical role in renal health and pathology [\u003cspan class=\"CitationRef\"\u003e152\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003c/div\u003e\n\u003ch2\u003ePresence or Role in Other Tumors:\u003c/h2\u003e\n\u003cp\u003eNOTCH2, a key player in cellular processes and development, is also entangled in the web of tumorigenesis and cancer progression across diverse cancer types [\u003cspan class=\"CitationRef\"\u003e153\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e154\u003c/span\u003e]. In colorectal cancer (CRC), NOTCH2 signaling emerges as a complex orchestrator, assuming a dual role as both a tumor suppressor and an oncogene. While it fosters cell differentiation and curtails proliferation, its aberrant activation can fuel CRC development by fostering tumor growth, invasion, and metastasis. Likewise, in breast cancer, NOTCH2 signaling influences disease progression and metastasis by governing crucial aspects of cancer cell behavior such as proliferation, survival, invasion, and stem cell properties [\u003cspan class=\"CitationRef\"\u003e155\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e156\u003c/span\u003e]. Dysregulated NOTCH2 signaling heralds aggressive breast cancer subtypes, dismal prognosis, and therapy resistance, prompting exploration of NOTCH2 inhibitors as potential therapeutic modalities. Moreover, in hepatocellular carcinoma (HCC), NOTCH2 signaling assumes a central role in driving tumorigenesis and progression. Its dysregulation in HCC orchestrates a cascade of events, including enhanced tumor cell proliferation, survival, invasion, and metastasis, thereby fueling tumor aggressiveness and therapeutic resistance. In pancreatic cancer, NOTCH2 signaling emerges as a formidable force propelling tumor initiation and advancement [\u003cspan class=\"CitationRef\"\u003e157\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e158\u003c/span\u003e]. Activation of NOTCH2 signaling fuels pancreatic cancer cell proliferation, survival, invasion, and metastasis, thereby contributing to poor patient prognosis and resistance to therapy, thereby underscoring its potential as a therapeutic target. In renal cell carcinoma (RCC), NOTCH2 signaling plays very important roles in disease evolution and progression. Dysregulated NOTCH2 expression in RCC cells drives tumor cell proliferation, angiogenesis, and metastasis, ultimately culminating in aggressive disease manifestations and adverse patient outcomes, highlighting its significance as a prognostic marker and therapeutic target in RCC management [\u003cspan class=\"CitationRef\"\u003e159\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e160\u003c/span\u003e].\u003c/p\u003e\n\u003cdiv id=\"Sec37\" class=\"Section2\"\u003e\n\u003ch2\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC:\u003c/h2\u003e\n\u003cp\u003eNOTCH2 signaling, crucial for maintaining hepatocyte identity and function, may falter in HCC, disrupting the normal genetic programming of hepatocytes. This disruption could lead to the downregulation or loss of hepatocyte-specific genes, fostering a cellular milieu conducive to transdifferentiation into other cell types, thus fostering tumor heterogeneity [\u003cspan class=\"CitationRef\"\u003e161\u003c/span\u003e]. Furthermore, dysregulated NOTCH2 expression in HCC may spur the activation of alternative differentiation pathways or lineage-specifying transcription factors. By invoking programs associated with intestinal epithelial cells or pancreatic progenitor cells, NOTCH2 dysregulation might drive transdifferentiation of HCC cells into phenotypes resembling these lineages. Moreover, NOTCH2 signaling's role in regulating cellular plasticity and fate determination is pertinent. Dysregulated NOTCH2 expression might disrupt the delicate balance between self-renewal and differentiation, heightening cellular plasticity within the HCC microenvironment and facilitating the adoption of alternative cell fates, thereby contributing to intratumoral heterogeneity [\u003cspan class=\"CitationRef\"\u003e162\u003c/span\u003e]. Additionally, dysregulated NOTCH2 expression in HCC may perturb signaling pathways involved in cell fate determination and differentiation. Crosstalk between NOTCH2 signaling and pathways like Wnt/\u0026beta;-catenin and TGF-\u0026beta; could lead to aberrant pathway activation, further promoting transdifferentiation and augmenting tumor heterogeneity. Finally, the interplay of NOTCH2 with other transcription factors and co-regulators is important. Dysregulated NOTCH2 expression might disrupt these interactions, culminating in aberrant activation or repression of downstream target genes, thus contributing to the emergence of transdifferentiation and heterogeneity features within HCC tumors [\u003cspan class=\"CitationRef\"\u003e163\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e164\u003c/span\u003e].\u003c/p\u003e\n\u003cdiv id=\"Sec38\" class=\"Section3\"\u003e\n\u003ch2\u003e9. HNF6\u003c/h2\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec39\" class=\"Section3\"\u003e\n\u003ch2\u003eExpression in Other Cell-Types:\u003c/h2\u003e\n\u003cp\u003eHNF6 (Hepatocyte Nuclear Factor 6), also referred to as ONECUT1, stands as a significant transcription factor primarily acknowledged for its significant roles in hepatocyte development and functionality. Nevertheless, its influence extends beyond hepatocytes, encompassing crucial involvement in the development of various other cell types: In pancreatic development, HNF6 orchestrates the differentiation of both endocrine and exocrine cell lineages. It holds a critical sway over the development of beta cells, responsible for insulin secretion, alongside other endocrine cell variants like alpha and delta cells [\u003cspan class=\"CitationRef\"\u003e165\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e166\u003c/span\u003e]. Additionally, HNF6 shapes the differentiation landscape of pancreatic exocrine cells, including acinar cells and ductal cells, thus contributing to the structural and functional integrity of the pancreas. Moreover, HNF6 emerges as a key player in the development and sustenance of biliary epithelial cells, which furnish the bile ducts and contribute to bile production and excretion. Its regulatory control over genes governing bile duct formation, bile acid metabolism, and epithelial cell differentiation within the liver and bile ducts underscores its indispensability in bile duct development and the onset of cholangiopathies [\u003cspan class=\"CitationRef\"\u003e167\u003c/span\u003e]. Furthermore, HNF6's expression in intestinal epithelial cells is essential for intestinal development and maintenance. It assumes responsibility for regulating genes that govern intestinal epithelial cell differentiation, barrier function, and mucosal immunity, ensuring the structural integrity of the intestinal lining and maintaining the delicate balance between epithelial cell proliferation and differentiation. In neuronal populations, particularly within the central nervous system, HNF6's presence directs neuronal differentiation and functionality. Its involvement in crucial processes like neuronal migration, axon guidance, and synaptic connectivity during brain development underscores its significance. However, dysregulated expression of HNF6 has been implicated in various neurodevelopmental disorders and neurodegenerative diseases [\u003cspan class=\"CitationRef\"\u003e168\u003c/span\u003e]. In adrenal gland development, HNF6 exercises regulatory control over the differentiation of adrenal cortex cells, particularly in the formation of steroidogenic cells. These cells, critical for the synthesis of hormones like cortisol and aldosterone, are crucial for adrenal gland morphogenesis and the initiation of steroid hormone production, thus highlighting the multidimensional role of HNF6 in adrenal gland development and functionality [\u003cspan class=\"CitationRef\"\u003e169\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec40\" class=\"Section3\"\u003e\n\u003ch2\u003ePresence or Role in Other Tumors:\u003c/h2\u003e\n\u003cp\u003eIn pancreatic cancer, HNF6's involvement has been underscored, influencing the regulation of genes pertinent to pancreatic cell differentiation and function. Dysregulated expression of HNF6 within this context may foster tumor initiation, progression, and metastasis, a correlation that aligns with poorer prognosis and aggressive tumor behavior among affected patients [\u003cspan class=\"CitationRef\"\u003e170\u003c/span\u003e]. Similarly, in colorectal cancer (CRC), HNF6's impact extends to the orchestration of intestinal epithelial cell dynamics. Perturbations in HNF6 expression levels have been noted, potentially influencing tumor development and progression. The expression levels of HNF6 correlate with critical parameters like tumor grade, metastatic potential, and patient survival, hinting at its promise as both a prognostic marker and a therapeutic target in CRC [\u003cspan class=\"CitationRef\"\u003e171\u003c/span\u003e]. Furthermore, in prostate cancer, HNF6 emerges as a significant player in disease trajectory, modulating genes crucial for prostate epithelial cell differentiation and function. Dysregulated HNF6 expression has been implicated in heightened cancer aggressiveness and metastatic potential, aligning with observations of its association with tumor stage, recurrence rates, and patient outcomes. In breast cancer, HNF6's presence in tumor tissues suggests its potential involvement in disease progression. Dysregulated expression of HNF6 correlates with indicators of aggressive tumor behavior, metastatic propensity, and patient prognosis. Its association with tumor grade, hormone receptor status, and patient survival underscores its relevance as a prognostic marker and therapeutic target in breast cancer management [\u003cspan class=\"CitationRef\"\u003e172\u003c/span\u003e]. In neuroendocrine tumors, HNF6's regulatory influence over neuroendocrine cell differentiation and function signifies its role in tumor development and progression within this context. Dysregulated HNF6 expression levels are implicated in tumor aggressiveness and hormone secretion, aligning with observations of its correlation with tumor grade, hormone secretion levels, and patient outcomes. This highlights its potential utility as a prognostic marker and therapeutic target in neuroendocrine tumors [\u003cspan class=\"CitationRef\"\u003e173\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e174\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eThe dysregulated expression of HNF6 in HCC can disturb the genetic blueprint essential for hepatocyte integrity, possibly leading to the attenuation or loss of hepatocyte-specific genes. Consequently, this deviation from the hepatocyte differentiation state could foster an environment conducive to transdifferentiation, thus fostering tumor heterogeneity [\u003cspan class=\"CitationRef\"\u003e175\u003c/span\u003e]. Furthermore, the aberrant expression of HNF6 may not only perturb the conventional differentiation pathways but also activate alternative programs or lineage-specifying factors within HCC cells. Drawing parallels with its role in pancreatic differentiation, dysregulation of HNF6 might propel HCC cells towards acquiring pancreatic-like phenotypes, thereby further enhancing tumor heterogeneity. Moreover, HNF6's involvement extends to the regulation of cellular plasticity and fate determination. In the context of HCC, dysregulated HNF6 expression could disrupt the delicate equilibrium between self-renewal and differentiation, thereby augmenting cellular plasticity. This augmented plasticity may empower HCC cells to adopt diverse cellular identities, thereby contributing to intratumoral heterogeneity [\u003cspan class=\"CitationRef\"\u003e176\u003c/span\u003e]. Additionally, dysregulated HNF6 expression in HCC could disrupt signaling pathways important for cell fate determination and differentiation. HNF6 crosstalks with pathways like Wnt/\u0026beta;-catenin and TGF-\u0026beta;, its dysregulation might trigger aberrant pathway activation, fostering transdifferentiation events and fueling tumor heterogeneity. Finally, HNF6's interactions with various transcription factors and co-regulators play a crucial role in governing gene expression networks crucial for cell fate decisions. In the context of HCC, dysregulated HNF6 expression could perturb these interactions, resulting in aberrant downstream gene regulation. This dysregulation may culminate in the emergence of transdifferentiation events and contribute significantly to the heterogeneity observed within HCC tumors [\u003cspan class=\"CitationRef\"\u003e177\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e178\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e10. ONECUT2/ HNF6\u0026beta;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExpression in Other Cell-Types\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eONECUT2, also known as HNF6\u0026beta;, extends its influence beyond hepatocytes, manifesting crucial roles in various cell types during development. In pancreatic progenitor cells, ONECUT2 orchestrates pancreatic development by steering the differentiation of both endocrine and exocrine cell lineages. It fosters the emergence of vital endocrine cell types like insulin-producing beta cells, glucagon-producing alpha cells, and somatostatin-producing delta cells [\u003cspan class=\"CitationRef\"\u003e179\u003c/span\u003e]. Additionally, ONECUT2 contributes to the formation of pancreatic exocrine cells such as acinar and ductal cells, essential for digestive enzyme secretion and pancreatic fluid homeostasis. Within the central nervous system, ONECUT2 exerts its influence during neuronal development. By guiding neuronal differentiation and axonal growth, it facilitates the establishment of neuronal circuits and synaptic connections. These actions contribute to the development of diverse neuronal subtypes crucial for sensory and motor functions, including motor neurons, interneurons, and sensory neurons [\u003cspan class=\"CitationRef\"\u003e180\u003c/span\u003e]. In intestinal epithelial cells, ONECUT2 regulates intestinal development and maintenance. It steers the differentiation of intestinal stem cells into specialized epithelial cell types like absorptive enterocytes and secretory goblet cells. Moreover, ONECUT2 bolsters intestinal barrier function and mucosal immunity, safeguarding against microbial intrusion and preserving intestinal equilibrium. Within the adrenal cortex, ONECUT2 participates in adrenal gland development by overseeing the differentiation of steroidogenic cells. These cells, nestled in distinct zones like the zona glomerulosa and zona fasciculata, synthesize essential steroid hormones like cortisol and aldosterone, thereby contributing to systemic homeostasis. Finally, in renal tubular epithelial cells, ONECUT2 plays a crucial role in kidney development [\u003cspan class=\"CitationRef\"\u003e181\u003c/span\u003e]. By regulating the differentiation of nephron progenitor cells into various renal tubular epithelial cell types, it ensures the formation of proximal tubule cells, distal tubule cells, and collecting duct cells. Furthermore, ONECUT2 upholds renal tubular integrity and function, essential for maintaining electrolyte balance and fluid homeostasis [\u003cspan class=\"CitationRef\"\u003e182\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePresence or Role in Other Tumors\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eONECUT2, also termed HNF6\u0026beta;, emerges as a significant player in the context of tumorigenesis and tumor progression across a spectrum of cancer types. In pancreatic cancer, ONECUT2 exhibits elevated expression levels, thereby fostering tumor growth, invasion, and metastasis by orchestrating the activation of genes governing proliferation, survival, and epithelial-mesenchymal transition (EMT). The heightened ONECUT2 expression correlates with dismal prognostic outcomes and reduced survival rates among pancreatic cancer patients [\u003cspan class=\"CitationRef\"\u003e183\u003c/span\u003e]. Similarly, in colorectal cancer, ONECUT2 is overexpressed, exerting its influence on tumor cell behavior by fueling proliferation, migration, and invasion through the regulation of key genes involved in cell cycle control, apoptosis resistance, and EMT. Elevated ONECUT2 levels align with advanced tumor stage, lymph node metastasis, and inferior prognosis in colorectal cancer patients [\u003cspan class=\"CitationRef\"\u003e184\u003c/span\u003e]. Prostate cancer presents another arena where ONECUT2 expression escalates, fostering tumor cell proliferation, survival, and androgen receptor (AR) signaling, thereby steering disease progression. Its regulatory influence extends to genes important for hormone response, cell cycle regulation, and metastasis, correlating with aggressive tumor phenotypes, biochemical recurrence, and castration-resistant prostate cancer (CRPC). In breast cancer, ONECUT2 emerges as an upregulated entity, perpetuating tumor cell proliferation, invasion, and metastasis by orchestrating gene networks governing cell cycle progression, angiogenesis, and tumor microenvironment remodeling [\u003cspan class=\"CitationRef\"\u003e185\u003c/span\u003e]. Its heightened expression is associated with adverse prognostic indicators, metastatic dissemination, and resistance to therapy among breast cancer cohorts. In neuroendocrine tumors, ONECUT2 assumes an augmented expression profile, where it modulates genes instrumental in neuroendocrine cell differentiation and function. This phenomenon culminates in heightened tumor cell proliferation, hormone secretion, and metastatic propensity, aligning with advanced tumor stage, hormone hypersecretion, and compromised patient outcomes [\u003cspan class=\"CitationRef\"\u003e186\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003eONECUT2 emerges as a significant contributor to tumorigenesis and tumor progression across diverse cancer types, exerting its influence through gene regulatory networks that dictate crucial aspects of cancer cell behavior and disease trajectory [\u003cspan class=\"CitationRef\"\u003e187\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eONECUT2/HNF6\u0026beta;, a critical regulator of hepatocyte development and function, holds sway over the genetic programming essential for maintaining the identity of hepatocytes. In the context of HCC, aberrant expression of ONECUT2/HNF6\u0026beta; may perturb this delicate balance, resulting in the downregulation or loss of hepatocyte-specific genes, thereby paving the way for a cellular milieu conducive to transdifferentiation into alternative cell types, thereby fostering heterogeneity within the tumor [\u003cspan class=\"CitationRef\"\u003e188\u003c/span\u003e]. Moreover, dysregulated expression of ONECUT2/HNF6\u0026beta; in HCC cells could instigate the activation of alternative differentiation pathways or lineage-specifying transcription factors, drawing parallels from its involvement in pancreatic cell differentiation and function. This aberration may propel the transdifferentiation of HCC cells towards acquiring a pancreatic-like phenotype, thereby augmenting the spectrum of cellular diversity within the tumor microenvironment. Furthermore, ONECUT2/HNF6\u0026beta;'s involvement in regulating cellular plasticity and fate determination unveils another layer of complexity. Dysregulation of its expression in HCC may disrupt the equilibrium between self-renewal and differentiation, fostering an environment conducive to enhanced cellular plasticity [\u003cspan class=\"CitationRef\"\u003e189\u003c/span\u003e]. This phenomenon could empower HCC cells with the ability to adopt alternative cell fates, thereby fueling the inherent heterogeneity observed within the tumor. Additionally, dysregulated expression of ONECUT2/HNF6\u0026beta; in HCC holds the potential to impinge upon signaling pathways crucial for cell fate determination and differentiation [\u003cspan class=\"CitationRef\"\u003e190\u003c/span\u003e]. Through crosstalk with pathways such as Wnt/\u0026beta;-catenin and TGF-\u0026beta;, dysregulation of ONECUT2/HNF6\u0026beta; may trigger aberrant activation of these pathways, thereby orchestrating transdifferentiation processes and contributing to the heterogeneous landscape within the tumor microenvironment. Moreover, the interplay of ONECUT2/HNF6\u0026beta; with other transcription factors and co-regulators underscores its role in orchestrating gene expression networks important for cell differentiation and function. Dysregulated expression of ONECUT2/HNF6\u0026beta; in HCC may perturb these interactions, culminating in aberrant activation or repression of downstream target genes, thus potentiating the emergence of transdifferentiation and heterogeneity features within the tumor microenvironment [\u003cspan class=\"CitationRef\"\u003e191\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e192\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e11. TBX3/18\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExpression in Other Cell-Types\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eTBX3 and TBX18, members of the T-box transcription factor family, exert important roles in embryonic development, extending beyond hepatocytes to various other cell types. In cardiac cells, TBX3 and TBX18 are instrumental in shaping the architecture of the heart [\u003cspan class=\"CitationRef\"\u003e193\u003c/span\u003e]. TBX3 contributes to the specification of pacemaker cells within the sinoatrial node, thus regulating heart rhythm, while TBX18 plays a crucial role in the differentiation and sustenance of cardiomyocytes, essential for cardiac function and the formation of the cardiac conduction system. These transcription factors also exert influence over the musculoskeletal system, participating in the development and differentiation of skeletal muscle, bone, and cartilage. TBX3 influences muscle development and regeneration, as well as skeletal patterning during limb formation, whereas TBX18 is vital for skeletal muscle and bone development, along with the specification of cartilage progenitor cells during embryogenesis [\u003cspan class=\"CitationRef\"\u003e194\u003c/span\u003e]. Furthermore, TBX3 and TBX18 contribute significantly to the formation of urogenital structures, including the kidneys, bladder, and reproductive organs. TBX3 aids in the formation of the ureteric bud and branching morphogenesis of the kidney, as well as the development of the bladder and urethra, whereas TBX18 is involved in the differentiation of smooth muscle cells in the urinary tract and reproductive organs. In neural crest-derived cells, TBX3 and TBX18 play crucial roles in the development of craniofacial structures, peripheral neurons, and melanocytes [\u003cspan class=\"CitationRef\"\u003e195\u003c/span\u003e]. TBX3 is integral to the patterning of craniofacial tissues and the specification of neural crest-derived cell lineages, while TBX18 contributes to the development of sensory neurons, glial cells in the peripheral nervous system, and the migration and differentiation of melanocytes. Moreover, TBX3 and TBX18 are implicated in the development of lymphatic vessels and lymphatic endothelial cells, crucial for immune function and tissue fluid homeostasis. TBX3 governs the specification and maintenance of lymphatic endothelial cell identity, as well as lymphangiogenesis, while TBX18 participates in the differentiation of lymphatic endothelial cells from venous endothelial precursors, thereby contributing to the formation of the lymphatic vasculature [\u003cspan class=\"CitationRef\"\u003e196\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePresence or Role in Other Tumors\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eTBX3 and TBX18, both important in embryonic development as transcription factors, extend their influence to tumorigenesis and tumor progression across various cancer types. In breast cancer, TBX3's overexpression is linked to tumor advancement and metastasis, as it governs genes involved in cell proliferation, epithelial-to-mesenchymal transition (EMT), and metastasis, thereby influencing patient prognosis [\u003cspan class=\"CitationRef\"\u003e197\u003c/span\u003e]. Similarly, TBX3 plays a significant role in melanoma progression and metastasis, regulating genes crucial for cell proliferation, invasion, and migration. Its heightened expression in melanoma tumors, particularly in metastatic lesions, correlates with advanced tumor stage and poor patient prognosis. In bladder cancer, elevated TBX3 expression levels are associated with tumor aggressiveness and adverse clinical outcomes, as it modulates genes governing cell proliferation, invasion, and metastasis, highlighting its significance in disease progression [\u003cspan class=\"CitationRef\"\u003e198\u003c/span\u003e]. Dysregulation of TBX3 expression in lung cancer, especially non-small cell lung cancer (NSCLC), underscores its role in tumor proliferation, invasion, and metastasis, with its expression levels being indicative of tumor grade, lymph node involvement, and patient survival. Conversely, TBX18's involvement in prostate cancer is important, where its altered expression correlates with tumor aggressiveness, recurrence, and poor patient outcomes, as it regulates genes pertinent to cell proliferation, invasion, and metastasis. Moreover, in colorectal cancer (CRC), dysregulated expression levels of both TBX3 and TBX18 contribute to tumor progression and metastasis, influencing genes related to cell proliferation, invasion, and metastasis, thereby affecting patient survival and disease outcome [\u003cspan class=\"CitationRef\"\u003e199\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eTBX3 and TBX18 are crucial in maintaining hepatocyte identity during development, essential for the normal genetic programing of hepatocytes. Dysregulated expression of TBX3/18 in hepatocellular carcinoma (HCC) may disrupt this programing, potentially leading to the downregulation or loss of hepatocyte-specific genes. Consequently, this loss of differentiation state could foster a cellular environment conducive to transdifferentiation into other cell types, thereby augmenting heterogeneity within the tumor [\u003cspan class=\"CitationRef\"\u003e200\u003c/span\u003e]. Furthermore, dysregulated TBX3/18 expression in HCC cells might activate alternative differentiation pathways or lineage-specifying transcription factors. For instance, TBX3's involvement in cardiac and musculoskeletal cell development, along with TBX18's role in cardiac and urogenital cell development, suggests their potential to induce alternative differentiation programs in HCC cells. This could lead to the transdifferentiation of HCC cells into cell types characteristic of other tissues. Moreover, TBX3 and TBX18 are implicated in regulating cellular plasticity and fate determination across various cell types. Their dysregulated expression in HCC could disrupt the balance between self-renewal and differentiation, resulting in enhanced cellular plasticity [\u003cspan class=\"CitationRef\"\u003e201\u003c/span\u003e]. Consequently, HCC cells may acquire the ability to adopt alternative cell fates, contributing further to tumor heterogeneity. Additionally, dysregulated TBX3/18 expression in HCC may influence signaling pathways crucial for cell fate determination and differentiation. Their interaction with signaling pathways such as Wnt/\u0026beta;-catenin, which is implicated in HCC pathogenesis, suggests a potential role in promoting transdifferentiation and heterogeneity within the tumor microenvironment. Furthermore, the interplay between TBX3/18 and other transcription factors and co-regulators is critical for regulating gene expression networks involved in cell differentiation and function [\u003cspan class=\"CitationRef\"\u003e202\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e203\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e12. Wnt/\u0026beta;-catenin pathway\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExpression in Other Cell-Types\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eThe Wnt/\u0026beta;-catenin signaling pathway stands as a regulator of development and homeostasis across various cell types, extending beyond hepatocytes. In embryonic stem cells (ESCs), this pathway assumes a crucial role in maintaining pluripotency and self-renewal [\u003cspan class=\"CitationRef\"\u003e204\u003c/span\u003e]. Activation of Wnt signaling fosters ESC proliferation while preventing differentiation, thus preserving the undifferentiated state. Within the developing nervous system, the Wnt/\u0026beta;-catenin pathway governs the proliferation, differentiation, and migration of neural progenitor cells (NPCs). Activation of Wnt signaling expands neural progenitor cell populations and orchestrates the specification of neuronal and glial lineages [\u003cspan class=\"CitationRef\"\u003e205\u003c/span\u003e]. For osteoblasts and chondrocytes, the Wnt/\u0026beta;-catenin pathway plays critical roles in skeletal development and bone homeostasis. It governs the proliferation and differentiation of osteoblast progenitors, promoting bone formation, and regulates chondrocyte differentiation, crucial for cartilage development and endochondral ossification. In the intestinal epithelium, the Wnt/\u0026beta;-catenin pathway is indispensable for development and maintenance [\u003cspan class=\"CitationRef\"\u003e206\u003c/span\u003e]. It oversees the proliferation and differentiation of intestinal stem cells within the crypts, fostering epithelial cell renewal and tissue regeneration. Dysregulation of Wnt signaling in intestinal epithelial cells is associated with intestinal disorders and colorectal cancer. Regarding hair follicle stem cells, the Wnt/\u0026beta;-catenin pathway regulates their activation, proliferation, and differentiation in the skin. Activation of Wnt signaling supports hair follicle regeneration and hair growth, while its inhibition precipitates hair follicle degeneration and alopecia. In the realm of immune cells, the Wnt/\u0026beta;-catenin pathway plays a multifactorial role in development and function. It oversees immune cell differentiation, activation, and effector functions across T cells, B cells, and dendritic cells, thereby contributing to both innate and adaptive immune responses [\u003cspan class=\"CitationRef\"\u003e207\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePresence or Role in Other Tumors\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eThe Wnt/\u0026beta;-catenin signaling pathway emerges as a frequent target of dysregulation in various tumors, significantly contributing to tumorigenesis, tumor progression, and metastasis. In colorectal cancer (CRC), dysregulation of the Wnt/\u0026beta;-catenin pathway stands as a hallmark, characterized by mutations in APC, CTNNB1 (encoding \u0026beta;-catenin), or other pathway components. These mutations lead to aberrant activation of Wnt signaling, fostering tumor initiation and progression [\u003cspan class=\"CitationRef\"\u003e208\u003c/span\u003e]. Activation of Wnt signaling fuels the proliferation, survival, and invasion of CRC cells, correlating with poor prognosis. Similarly, in hepatocellular carcinoma (HCC), frequent activation of the Wnt/\u0026beta;-catenin pathway contributes significantly to hepatocarcinogenesis. Mutations in CTNNB1 or AXIN1, resulting in \u0026beta;-catenin stabilization and nuclear translocation, are prevalent in HCC. This activation promotes HCC cell proliferation, survival, and metastasis, correlating with tumor aggressiveness and unfavorable patient outcomes. Dysregulated Wnt/\u0026beta;-catenin signaling is also implicated in various subtypes of breast cancer, where its activation promotes cell proliferation, survival, and metastasis [\u003cspan class=\"CitationRef\"\u003e209\u003c/span\u003e]. The crosstalk between Wnt signaling and hormone receptor pathways, such as the estrogen receptor and HER2, contributes to endocrine therapy resistance and tumor recurrence. In lung cancer, particularly non-small cell lung cancer (NSCLC), aberrant activation of the Wnt/\u0026beta;-catenin pathway is frequently observed. Mutations in Wnt pathway components or alterations in Wnt ligand expression disrupt Wnt signaling regulation, fostering NSCLC cell proliferation, invasion, and resistance to therapy, correlating with advanced tumor stage and poor patient outcomes. Moreover, dysregulated Wnt/\u0026beta;-catenin signaling plays a significant role in pancreatic cancer progression. Mutations in Wnt pathway components or alterations in Wnt ligand expression drive aberrant activation of Wnt signaling in pancreatic cancer cells, promoting proliferation, invasion, and metastasis, and correlating with tumor aggressiveness and poor patient prognosis [\u003cspan class=\"CitationRef\"\u003e210\u003c/span\u003e]. In melanoma, the Wnt/\u0026beta;-catenin pathway is also dysregulated, contributing to disease progression and metastasis. Activation of Wnt signaling promotes melanoma cell proliferation, survival, and invasion, correlating with tumor aggressiveness and unfavorable patient outcomes [\u003cspan class=\"CitationRef\"\u003e211\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eThe Wnt/\u0026beta;-catenin pathway stands out as an important regulator in maintaining hepatocyte identity and function. However, in hepatocellular carcinoma (HCC), dysregulated activation of this pathway can lead to the downregulation of hepatocyte-specific genes, resulting in the loss of hepatocyte identity. Consequently, this loss of differentiation state may create an environment conducive to transdifferentiation into other cell types, thereby contributing to the tumor's heterogeneity [\u003cspan class=\"CitationRef\"\u003e212\u003c/span\u003e]. Furthermore, dysregulated Wnt/\u0026beta;-catenin signaling in HCC cells can activate alternative differentiation pathways or lineage-specifying transcription factors. For instance, it has been associated with the upregulation of genes involved in epithelial-mesenchymal transition (EMT) and stemness, potentially driving transdifferentiation into mesenchymal-like or progenitor-like cell states, thus adding to the tumor's heterogeneity. Moreover, the Wnt/\u0026beta;-catenin pathway's role in regulating cellular plasticity and fate determination is critical. Dysregulated expression of this pathway in HCC may enhance cellular plasticity, enabling cells to adopt alternative fates. This plasticity fosters the emergence of heterogeneous cell populations within the tumor, including those with stem-like properties, further contributing to its complexity [\u003cspan class=\"CitationRef\"\u003e213\u003c/span\u003e]. Additionally, dysregulated Wnt/\u0026beta;-catenin signaling can influence the tumor microenvironment, altering interactions between cancer cells and stromal cells. Such alterations may promote the emergence of heterogeneous cell populations within the tumor and facilitate the transdifferentiation of HCC cells into cell types characteristic of other tissues, thereby amplifying heterogeneity [\u003cspan class=\"CitationRef\"\u003e214\u003c/span\u003e]. Furthermore, the interplay between the Wnt/\u0026beta;-catenin pathway and other signaling pathways implicated in cell fate determination and differentiation is significant. Dysregulated crosstalk between Wnt/\u0026beta;-catenin signaling and pathways such as Notch, Hedgehog, or TGF-\u0026beta; pathways in HCC may exacerbate the emergence of transdifferentiation and heterogeneity features, further complicating the tumor landscape [\u003cspan class=\"CitationRef\"\u003e215\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e216\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e217\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e13. FGF\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExpression in Other Cell-Types\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eFibroblast Growth Factors (FGFs) play roles in the development and maintenance of various cell types. In neural cells, FGFs are indispensable for the formation and sustenance of the nervous system, influencing processes such as proliferation, differentiation, and survival of neural progenitor cells, as well as guiding axonal growth and synaptic plasticity, thereby contributing significantly to neurogenesis and gliogenesis [\u003cspan class=\"CitationRef\"\u003e218\u003c/span\u003e]. Mesenchymal cells also rely on FGFs for their development and differentiation into different lineages like osteoblasts, chondrocytes, and adipocytes. FGFs orchestrate processes such as bone formation, cartilage development, and adipogenesis, crucial during skeletal development and tissue repair. Moreover, FGFs partake in wound healing, angiogenesis, and fibrosis, essential for tissue integrity and repair across various organs [\u003cspan class=\"CitationRef\"\u003e219\u003c/span\u003e]. Epithelial tissues, including those in the skin, lungs, and gastrointestinal tract, depend on FGFs for their development, maintenance, and repair. FGFs regulate epithelial cell behavior, governing proliferation, differentiation, migration, and tissue morphogenesis, contributing significantly to organogenesis and tissue homeostasis. Vascular endothelial cells rely on FGFs for angiogenesis and vascular development [\u003cspan class=\"CitationRef\"\u003e220\u003c/span\u003e]. These growth factors modulate endothelial cell functions such as proliferation, migration, tube formation, and blood vessel remodeling, critical for both embryonic vasculogenesis and postnatal vascular maintenance and repair. In muscle cells, FGFs play crucial roles in development and regeneration, particularly in skeletal and cardiac muscle. They regulate processes like myoblast proliferation, differentiation, and fusion, which are vital for muscle growth, repair, and function throughout life. Finally, FGFs exert influence on the development and function of various immune cell types [\u003cspan class=\"CitationRef\"\u003e221\u003c/span\u003e]. They regulate immune cell proliferation, differentiation, and activation, as well as cytokine production and inflammatory responses. FGFs contribute to immune cell development in primary lymphoid organs and modulate immune cell trafficking and function in peripheral tissues, thereby playing crucial roles in immune system homeostasis and responses [\u003cspan class=\"CitationRef\"\u003e222\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePresence or Role in Other Tumors\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eFibroblast Growth Factors (FGFs) and their signaling pathways have significant implications in tumorigenesis, tumor progression, and metastasis across various types of cancers. In breast cancer, FGF signaling is frequently dysregulated, with overexpression of FGF ligands and receptors like FGF1, FGF2, and FGFR1 associated with tumor growth, angiogenesis, and metastasis [\u003cspan class=\"CitationRef\"\u003e223\u003c/span\u003e]. This signaling cascade promotes breast cancer cell proliferation, survival, invasion, and resistance to therapy, ultimately correlating with poor prognosis. Similarly, dysregulated FGF signaling is evident in lung cancer, particularly in non-small cell lung cancer (NSCLC), where alterations in FGF ligands such as FGF2 and FGFRs contribute to tumorigenesis and progression. FGF signaling in NSCLC fosters cell proliferation, angiogenesis, and metastasis, linking to advanced tumor stage and unfavorable patient outcomes. In colorectal cancer (CRC), FGF signaling plays a crucial role in tumor development and progression, with upregulation of FGF ligands like FGF18 and FGFR4 observed in CRC tumors [\u003cspan class=\"CitationRef\"\u003e224\u003c/span\u003e]. This signaling axis promotes CRC cell proliferation, survival, angiogenesis, and invasion, fueling tumor growth and metastasis. Prostate cancer pathogenesis involves dysregulated FGF signaling, characterized by the overexpression of FGF ligands such as FGF8 and FGFR1. This dysregulation contributes to tumor growth, angiogenesis, and progression to castration-resistant prostate cancer (CRPC). FGF signaling drives prostate cancer cell proliferation, survival, and invasion, presenting a potential therapeutic target in CRPC. Pancreatic cancer also exhibits dysregulated FGF signaling, with overexpression of FGF ligands such as FGF2 and FGF19, along with FGFRs, observed in pancreatic tumors [\u003cspan class=\"CitationRef\"\u003e225\u003c/span\u003e]. This aberrant signaling promotes pancreatic cancer cell proliferation, survival, angiogenesis, and metastasis, aligning with poor patient outcomes. In melanoma, dysregulated FGF signaling contributes to tumor progression and therapy resistance, with alterations in FGF ligands like FGF2 and FGFRs detected in melanoma tumors. This signaling pathway promotes melanoma cell proliferation, survival, angiogenesis, and invasion, correlating with tumor aggressiveness and unfavorable prognosis [\u003cspan class=\"CitationRef\"\u003e226\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eFGF signaling pathways exhibit the capability to induce alternative differentiation programs in HCC cells, potentially leading to the transdifferentiation of these cells into mesenchymal-like or stem-like states. This induction of alternative pathways can contribute significantly to the heterogeneity within the tumor by generating cell populations with distinct phenotypic and functional characteristics [\u003cspan class=\"CitationRef\"\u003e227\u003c/span\u003e]. Moreover, dysregulated FGF expression in HCC can enhance cellular plasticity, allowing tumor cells to adopt alternative cell fates in response to microenvironmental cues or signaling inputs. This heightened plasticity often results in the emergence of diverse cell populations within the tumor, including those exhibiting stem-like properties or alternative lineage markers. Furthermore, FGF signaling can influence the tumor microenvironment by modulating interactions between cancer cells and stromal cells. In HCC, dysregulated FGF expression may alter the composition and function of the tumor microenvironment, fostering the emergence of heterogeneity [\u003cspan class=\"CitationRef\"\u003e228\u003c/span\u003e]. For instance, FGF signaling can stimulate processes like angiogenesis, fibrosis, and immune cell recruitment, creating supportive niches for distinct subpopulations of HCC cells. Additionally, FGF signaling has been implicated in the activation of epithelial-mesenchymal transition (EMT), a process associated with increased cellular plasticity and invasive behavior in cancer cells. Dysregulated FGF expression in HCC may induce EMT in certain tumor cells, leading to the acquisition of mesenchymal features and further contributing to tumor heterogeneity, progression, metastasis, and resistance to therapy [\u003cspan class=\"CitationRef\"\u003e229\u003c/span\u003e]. Moreover, FGF signaling pathways interplay with other signaling pathways involved in cell fate determination and differentiation. Perturbations in FGF expression in HCC can disrupt the balance of these pathways, leading to the emergence of transdifferentiation and heterogeneity features. For example, interactions between FGF and Wnt/\u0026beta;-catenin signaling pathways have been documented in HCC, highlighting their implications for tumor cell plasticity and heterogeneity [\u003cspan class=\"CitationRef\"\u003e230\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e231\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e14. HGF\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExpression in Other Cell-Types\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eHepatocyte Growth Factor (HGF), also known as scatter factor, exhibits various roles in the development and maintenance of multiple cell types beyond hepatocytes. HGF serves as mitogen for epithelial cells, regulating branching morphogenesis and tubulogenesis in tissues like the lung, kidney, and mammary gland during development [\u003cspan class=\"CitationRef\"\u003e232\u003c/span\u003e]. It fosters the proliferation, survival, and migration of epithelial cells, thus contributing significantly to tissue morphogenesis and organ development. Moreover, HGF functions as a key regulator of angiogenesis and vascular development, stimulating endothelial cell proliferation, migration, and tube formation. This activity promotes the formation of new blood vessels during both embryonic development and tissue repair processes, ensuring proper vascularization of developing organs and maintaining vascular homeostasis in adult tissues [\u003cspan class=\"CitationRef\"\u003e233\u003c/span\u003e]. In addition, HGF acts as a paracrine factor for mesenchymal cells such as fibroblasts and smooth muscle cells, regulating their proliferation, migration, and differentiation. This influence extends to tissue remodeling, wound healing, and organ fibrosis, where HGF signaling plays key roles in orchestrating mesenchymal-epithelial interactions during organ development and regeneration. Furthermore, HGF and its receptor, c-Met, are expressed in the nervous system, where they contribute to neurogenesis, neuronal migration, and synaptogenesis [\u003cspan class=\"CitationRef\"\u003e234\u003c/span\u003e]. HGF supports the proliferation and survival of neural progenitor cells and facilitates neurite outgrowth and branching, thus influencing the development and plasticity of neuronal circuits in the brain and spinal cord. Additionally, HGF signaling is implicated in myogenesis and muscle regeneration, promoting the proliferation and differentiation of myoblasts and facilitating muscle fiber formation and repair. It also regulates myoblast migration and fusion during embryonic development and in response to muscle injury, ensuring proper muscle growth and regeneration. HGF influences the function of various immune cell types, including macrophages, T cells, and dendritic cells, by regulating their migration, cytokine production, and tissue infiltration [\u003cspan class=\"CitationRef\"\u003e235\u003c/span\u003e]. This modulation of inflammatory responses and tissue repair processes contributes to immune cell recruitment to sites of injury or inflammation, ultimately aiding in tissue remodeling and regeneration. Overall, HGF plays diverse and crucial roles in the development and maintenance of multiple cell types, including epithelial, endothelial, mesenchymal, neural, muscle, and immune cells. Its signaling pathways are indispensable for tissue morphogenesis, organogenesis, and repair processes throughout the body [\u003cspan class=\"CitationRef\"\u003e236\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePresence or Role in Other Tumors\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eHepatocyte Growth Factor (HGF) and its receptor c-Met play significant roles in tumorigenesis, tumor progression, and metastasis across various types of cancers. In gastric cancer, dysregulated HGF/c-Met signaling is linked to disease progression and unfavorable prognosis. Gastric tumors often exhibit overexpression of HGF and c-Met, promoting tumor cell proliferation, invasion, and metastasis. Moreover, this signaling pathway contributes to angiogenesis and confers resistance to chemotherapy in gastric cancer cases. Similarly, in breast cancer, HGF/c-Met signaling is associated with metastasis and resistance to therapy. Elevated levels of HGF and c-Met are correlated with aggressive cancer phenotypes and adverse patient outcomes [\u003cspan class=\"CitationRef\"\u003e237\u003c/span\u003e]. This signaling axis facilitates breast cancer cell migration, invasion, and metastasis to distant sites such as the lung and bone, while also fostering resistance to targeted therapies like HER2 inhibitors and endocrine therapy. In non-small cell lung cancer (NSCLC), dysregulated HGF/c-Met signaling is particularly important in cases of acquired resistance to EGFR inhibitors. Overexpression of HGF and c-Met correlates with tumor progression, metastasis, and poor prognosis among NSCLC patients. The pathway promotes NSCLC cell proliferation, survival, invasion, and resistance to targeted therapies, including EGFR inhibitors and immune checkpoint inhibitors [\u003cspan class=\"CitationRef\"\u003e238\u003c/span\u003e]. Moreover, HGF/c-Met signaling is implicated in colorectal cancer (CRC) progression and metastasis. Elevated levels of HGF and c-Met are associated with advanced tumor stage, lymph node metastasis, and unfavorable prognosis in CRC patients. This signaling axis drives CRC cell proliferation, invasion, and metastasis to distant organs like the liver, contributing to resistance against chemotherapy and targeted therapies. Similarly, dysregulated HGF/c-Met signaling is observed in pancreatic cancer, promoting tumor progression, invasion, and metastasis. Overexpression of HGF and c-Met is linked to aggressive cancer phenotypes and poor patient outcomes in pancreatic cancer cases. The pathway facilitates pancreatic cancer cell proliferation, survival, angiogenesis, and metastasis to the liver and peritoneum, while also conferring resistance to chemotherapy and targeted therapies [\u003cspan class=\"CitationRef\"\u003e239\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eHepatocyte Growth Factor (HGF) plays a crucial role in promoting tumor heterogeneity and progression in Hepatocellular Carcinoma (HCC) through various mechanisms. HGF acts as an inducer of Epithelial-Mesenchymal Transition (EMT), prompting epithelial cells to lose their distinctive features and adopt mesenchymal traits. In HCC, dysregulated HGF expression triggers EMT in hepatocytes, resulting in the loss of hepatocyte-specific characteristics and the acquisition of mesenchymal properties [\u003cspan class=\"CitationRef\"\u003e240\u003c/span\u003e]. This transition enhances cellular plasticity, fostering the emergence of diverse cell populations within the tumor. Moreover, HGF signaling pathways can activate alternative differentiation programs in HCC cells. By stimulating the expression of lineage-specific transcription factors and signaling molecules, HGF drives the transdifferentiation of hepatocytes into other cell types, such as progenitor-like cells or mesenchymal cells. This transdifferentiation process contributes to tumor heterogeneity and may fuel tumor progression and resistance to therapy. Additionally, HGF enhances cellular plasticity by promoting stemness and dedifferentiation in HCC cells [\u003cspan class=\"CitationRef\"\u003e241\u003c/span\u003e]. Dysregulated HGF expression increases the stem-like properties of tumor cells, enabling them to adopt multiple cell fates and contribute to tumor heterogeneity. This enhanced cellular plasticity facilitates the emergence of therapy-resistant cell populations within the tumor. Furthermore, HGF can modulate the tumor microenvironment by stimulating the recruitment and activation of stromal cells, such as fibroblasts and immune cells [\u003cspan class=\"CitationRef\"\u003e242\u003c/span\u003e]. Dysregulated HGF expression alters the composition and function of the tumor microenvironment, creating niches that support the survival and proliferation of heterogeneous cell populations. This microenvironmental modulation sustains tumor heterogeneity and promotes tumor progression. HGF signaling pathways crosstalk with other signaling pathways involved in cell fate determination and differentiation [\u003cspan class=\"CitationRef\"\u003e243\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e244\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e15. TGF-\u0026beta;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExpression in Other Cell-Types\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eTransforming Growth Factor-beta (TGF-\u0026beta;) is a multifunctional molecule involved in the development and maintenance of various cell types throughout the body. TGF-\u0026beta; serves as a crucial regulator of epithelial cell behavior, controlling differentiation, proliferation, and homeostasis [\u003cspan class=\"CitationRef\"\u003e245\u003c/span\u003e]. It orchestrates epithelial-mesenchymal interactions during development, facilitating the formation of organs like the lung, skin, and mammary gland. By promoting epithelial cell differentiation while inhibiting proliferation, TGF-\u0026beta; contributes significantly to tissue morphogenesis and organ development. In mesenchymal cells, TGF-\u0026beta; signaling is vital for differentiation, migration, and matrix deposition. It guides the differentiation of mesenchymal stem cells into specialized cell types such as osteoblasts, chondrocytes, and adipocytes, essential for skeletal development and tissue repair. Moreover, TGF-\u0026beta; stimulates fibroblast activation and collagen production, key processes in tissue remodeling, wound healing, and fibrotic conditions. TGF-\u0026beta; signaling is indispensable for vascular development and angiogenesis, crucial for the formation of new blood vessels during embryogenesis and tissue repair [\u003cspan class=\"CitationRef\"\u003e246\u003c/span\u003e]. It regulates endothelial cell behaviors like proliferation, migration, and tube formation, facilitating vascular growth and maturation. Additionally, TGF-\u0026beta; modulates interactions between endothelial cells and pericytes, as well as the deposition of basement membrane components, promoting vascular stability. In the immune system, TGF-\u0026beta; plays critical roles in cell differentiation, activation, and function. It regulates the differentiation of T cells, B cells, and macrophages, along with cytokine production and immune responses. Acting as an immune suppressor, TGF-\u0026beta; dampens inflammation and fosters immune tolerance in peripheral tissues [\u003cspan class=\"CitationRef\"\u003e247\u003c/span\u003e]. Dysregulated TGF-\u0026beta; signaling is associated with conditions like autoimmune diseases and cancer immunosuppression. TGF-\u0026beta; signaling is also involved in neurogenesis, neuronal migration, and synaptogenesis within the developing nervous system. It guides the proliferation and differentiation of neural progenitor cells while influencing neurite outgrowth and branching. Additionally, TGF-\u0026beta; modulates synaptic plasticity and neurotransmitter release, contributing to the formation and function of neural circuits [\u003cspan class=\"CitationRef\"\u003e248\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePresence or Role in Other Tumors\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eTransforming Growth Factor-beta (TGF-\u0026beta;) signaling plays a key role in tumorigenesis and tumor progression across various cancer types. In breast cancer, TGF-\u0026beta; signaling exhibits a dual role, functioning as a tumor suppressor in early stages but promoting tumor progression in advanced stages. Initially, TGF-\u0026beta; inhibits epithelial cell proliferation and induces apoptosis, exerting tumor-suppressive effects [\u003cspan class=\"CitationRef\"\u003e249\u003c/span\u003e]. However, as breast cancer advances, cells often develop resistance to TGF-\u0026beta;'s growth-inhibitory actions and exploit its pro-metastatic functions. This leads to the promotion of epithelial-mesenchymal transition (EMT), invasion, and metastasis, contributing to tumor aggressiveness. Similarly, in colorectal cancer (CRC), dysregulated TGF-\u0026beta; signaling is a hallmark of disease progression. Initially, TGF-\u0026beta; acts as a tumor suppressor by inhibiting epithelial cell proliferation and promoting apoptosis. However, during CRC progression, mutations often disrupt TGF-\u0026beta; signaling, abolishing its tumor-suppressive effects and activating pro-metastatic pathways [\u003cspan class=\"CitationRef\"\u003e250\u003c/span\u003e]. Consequently, TGF-\u0026beta; promotes EMT, invasion, and metastasis, exacerbating tumor aggressiveness. In pancreatic cancer, dysregulated TGF-\u0026beta; signaling is frequently observed and associated with disease progression and metastasis. TGF-\u0026beta; promotes EMT, invasion, and metastasis in pancreatic tumors, while also stimulating the desmoplastic reaction and creating a tumor-promoting microenvironment. This dysregulation contributes to poor patient prognosis and therapeutic resistance [\u003cspan class=\"CitationRef\"\u003e251\u003c/span\u003e]. Similarly, in lung cancer, TGF-\u0026beta; signaling exhibits complex roles. Initially acting as a tumor suppressor by inhibiting epithelial cell proliferation and inducing apoptosis, it later contributes to tumor aggressiveness as cancer cells acquire mutations that disrupt TGF-\u0026beta; signaling. This results in the promotion of EMT, invasion, and metastasis, ultimately leading to poor patient outcomes. In prostate cancer, dysregulated TGF-\u0026beta; signaling is implicated in disease progression and metastasis. TGF-\u0026beta; promotes EMT, invasion, and metastasis in prostate cancer cells, while also modulating the tumor microenvironment to support angiogenesis, immune evasion, and therapy resistance. This dysregulation contributes to tumor aggressiveness and metastatic spread in prostate cancer patients [\u003cspan class=\"CitationRef\"\u003e252\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eDysregulated expression of Transforming Growth Factor-beta (TGF-\u0026beta;) in hepatocellular carcinoma (HCC) can lead to the emergence of transdifferentiation and heterogeneity features through various mechanisms, considering its roles in other cell types and tumors [\u003cspan class=\"CitationRef\"\u003e253\u003c/span\u003e]. TGF-\u0026beta; signaling serves as an inducer of epithelial-mesenchymal transition (EMT), prompting epithelial cells in HCC to lose their differentiated phenotype and acquire mesenchymal characteristics. This dysregulation triggers the loss of hepatocyte-specific features and the acquisition of mesenchymal traits, thereby increasing cellular plasticity and contributing to the emergence of heterogeneous cell populations within the tumor. Moreover, TGF-\u0026beta; signaling pathways can activate alternative differentiation programs in HCC cells by stimulating the expression of lineage-specific transcription factors and signaling molecules. This process drives the transdifferentiation of hepatocytes into other cell types, such as progenitor-like cells or mesenchymal cells, thereby generating cellular heterogeneity within the tumor and potentially fueling tumor progression and therapeutic resistance [\u003cspan class=\"CitationRef\"\u003e254\u003c/span\u003e]. Additionally, TGF-\u0026beta; is recognized for its ability to enhance cellular plasticity by promoting stemness and dedifferentiation across various cell types. In HCC, dysregulated expression of TGF-\u0026beta; may augment the stem-like properties of tumor cells, enabling them to adopt multiple cell fates and contribute to tumor heterogeneity. Consequently, TGF-\u0026beta;-induced cellular plasticity may facilitate the emergence of therapy-resistant cell populations within the tumor microenvironment. Furthermore, TGF-\u0026beta; can modulate the tumor microenvironment by influencing the behavior of stromal cells, including fibroblasts, endothelial cells, and immune cells. This dysregulation alters the composition and function of the tumor microenvironment, creating niches that support the survival and proliferation of heterogeneous cell populations, thus contributing to the maintenance of tumor heterogeneity and promoting tumor progression [\u003cspan class=\"CitationRef\"\u003e255\u003c/span\u003e]. Finally, TGF-\u0026beta; signaling pathways interact with other signaling pathways implicated in cell fate determination and differentiation, such as Wnt/\u0026beta;-catenin and Notch pathways. Dysregulated expression of TGF-\u0026beta; in HCC disrupts the balance of signaling pathways involved in maintaining hepatocyte identity and homeostasis, leading to the emergence of transdifferentiation and heterogeneity features. These interactions further exacerbate cellular plasticity and heterogeneity in HCC, contributing to tumor aggressiveness and progression [\u003cspan class=\"CitationRef\"\u003e256\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e257\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e258\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e16. Hippo signaling pathway\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExpression in Other Cell-Types\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eHippo signaling pathway, originally recognized for its involvement in regulating organ size and tissue growth, is fundamental for the development and maintenance of various cell types beyond hepatocytes. In epithelial cells, the Hippo pathway governs processes such as proliferation, differentiation, and polarity [\u003cspan class=\"CitationRef\"\u003e259\u003c/span\u003e]. Across different tissues like the skin, intestine, and lung, Hippo signaling orchestrates epithelial morphogenesis and ensures barrier function. Activation of the Hippo pathway represses genes associated with cell proliferation while promoting the establishment of apical-basal polarity, critical for the proper formation and sustenance of epithelial tissues. Furthermore, Hippo signaling exerts influence on mesenchymal cells, including fibroblasts, smooth muscle cells, and osteoblasts [\u003cspan class=\"CitationRef\"\u003e260\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e261\u003c/span\u003e]. During skeletal development, components of the Hippo pathway regulate the differentiation of mesenchymal stem cells into osteoblasts and chondrocytes, thereby contributing significantly to bone formation and remodeling. Additionally, Hippo signaling governs the contractility and migration of mesenchymal cells during tissue repair and organogenesis. In neural cells, Hippo signaling oversees neurogenesis, neuronal differentiation, and axon guidance within the developing nervous system. Particularly in the brain, components of the Hippo pathway control the proliferation and differentiation of neural progenitor cells, influencing cortical development and the formation of neuronal circuits [\u003cspan class=\"CitationRef\"\u003e262\u003c/span\u003e]. Moreover, Hippo signaling modulates synaptic plasticity and dendritic arborization, both critical for proper neural circuit function. The Hippo pathway also participates in vascular development and angiogenesis, particularly concerning endothelial cells. By regulating endothelial cell proliferation, migration, and tube formation, Hippo signaling contributes to the genesis of new blood vessels during embryogenesis and tissue repair. However, dysregulated Hippo signaling can disrupt vascular morphogenesis and contribute to pathological angiogenesis, as seen in conditions like cancer and retinopathy [\u003cspan class=\"CitationRef\"\u003e263\u003c/span\u003e]. Furthermore, Hippo signaling impacts the functionality of various immune cell types, encompassing T cells, B cells, and macrophages. Within the immune system, components of the Hippo pathway govern processes such as cell proliferation, differentiation, and cytokine production, thereby modulating immune responses and inflammation. Dysregulation of Hippo signaling has been associated with autoimmune diseases, cancer immunosuppression, and inflammatory disorders, highlighting its importance in immune regulation [\u003cspan class=\"CitationRef\"\u003e264\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePresence or Role in Other Tumors\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eThe Hippo signaling pathway, renowned for its role in regulating organ size and tissue growth during development, is also deeply involved in various tumors. In liver cancer (Hepatocellular carcinoma - HCC), dysregulated Hippo signaling is a common occurrence. This pathway, crucial for liver organ size and function, undergoes disruption in HCC, leading to aberrant activation of YAP (Yes-associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif), downstream effectors [\u003cspan class=\"CitationRef\"\u003e265\u003c/span\u003e]. Consequently, YAP/TAZ activation fosters hepatocyte proliferation, stemness, and resistance to apoptosis, thereby fueling HCC development and progression. Similarly, dysregulated Hippo signaling surfaces in breast cancer, contributing to its progression and metastasis. Abnormal YAP and TAZ activation in breast cancer cells promote cell proliferation, survival, epithelial-mesenchymal transition (EMT), and metastasis, correlating with aggressive phenotypes and poor patient outcomes. Moreover, Hippo signaling dysregulation in breast cancer leads to therapy resistance, underscoring its potential as a therapeutic target. Colorectal cancer (CRC) also exhibits dysregulated Hippo signaling, impacting tumor initiation and advancement. The activation of YAP and TAZ promotes CRC cell proliferation, invasion, and metastasis, correlating with adverse clinicopathological characteristics and poor prognosis [\u003cspan class=\"CitationRef\"\u003e266\u003c/span\u003e]. Furthermore, Hippo signaling modulation of the tumor microenvironment in CRC fosters angiogenesis, immune evasion, and therapy resistance. Likewise, in lung cancer, dysregulated Hippo signaling drives progression and metastasis. Aberrant YAP and TAZ activation in lung cancer cells fuel proliferation, EMT, invasion, and distant metastasis, aligning with aggressive tumor behavior and unfavorable patient outcomes. Moreover, dysregulated Hippo signaling contributes to therapy resistance in lung cancer, emphasizing its importance as a therapeutic target. In pancreatic cancer, dysregulated Hippo signaling promotes tumor progression and metastasis. Abnormal YAP and TAZ activation enhances pancreatic cancer cell proliferation, invasion, and metastasis to distant sites, correlating with poor prognosis and therapeutic resistance. Additionally, dysregulated Hippo signaling in pancreatic cancer shapes the tumor microenvironment, fostering desmoplasia and immune evasion [\u003cspan class=\"CitationRef\"\u003e267\u003c/span\u003e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDysregulated expression in the emergence of transdifferentiation and heterogeneity features in HCC\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eHippo pathway, crucial for regulating cell proliferation and apoptosis, is disrupted in HCC, leading to uncontrolled cell growth and tumor heterogeneity. This dysregulation results in varying levels of proliferation among different cells within the tumor, contributing to its heterogeneous nature. Furthermore, activation of the Hippo pathway, particularly through the downregulation of its effectors YAP and TAZ, inhibits stemness properties in hepatic stem cells. However, dysregulated Hippo signaling in HCC may induce stem-like characteristics in tumor cells, fostering a heterogeneous cell population with varying degrees of differentiation. Moreover, dysregulated Hippo signaling, leading to the activation of YAP and TAZ, is associated with the induction of EMT in cancer cells [\u003cspan class=\"CitationRef\"\u003e268\u003c/span\u003e]. This process involves epithelial cells losing their characteristics and acquiring mesenchymal traits, resulting in increased migratory and invasive properties and further contributing to tumor heterogeneity. Additionally, dysregulated Hippo signaling influences cell fate decisions and plasticity within HCC tumors. In response to changes in the tumor microenvironment or therapeutic pressures, HCC cells with altered Hippo signaling may undergo phenotypic switching between hepatocyte-like and progenitor-like states, adding to the observed heterogeneity. Furthermore, the Hippo pathway not only affects tumor cell behavior but also shapes the tumor microenvironment [\u003cspan class=\"CitationRef\"\u003e269\u003c/span\u003e]. Dysregulated Hippo signaling alters the crosstalk between tumor cells and stromal, immune, and vascular cells, leading to changes in the tumor microenvironment that contribute to tumor heterogeneity. Finally, the heterogeneity driven by dysregulated Hippo signaling can confer resistance to therapies. Subpopulations of cells with different Hippo pathway activity may respond differently to treatment, allowing for the survival and proliferation of resistant clones, further complicating therapeutic interventions [\u003cspan class=\"CitationRef\"\u003e270\u003c/span\u003e].\u003c/p\u003e\n\u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e \u003cb\u003eEmergence of HCC Heterogeneity and Transdifferentiation\u003c/b\u003e \u003c/p\u003e \u003cp\u003eHepatocellular carcinoma (HCC) is a highly heterogeneous malignancy characterized by diverse cellular phenotypes and molecular subtypes. Understanding the mechanisms driving HCC heterogeneity and transdifferentiation is crucial for developing effective therapeutic strategies and improving patient outcomes. In this discussion, we focus on key factors and pathways implicated in the emergence of HCC heterogeneity and transdifferentiation, including HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/Onecut1, ONECUT2/HNF6β, TBX3/18, Wnt/β-catenin pathway, FGF, HGF, TGF-β, and Hippo signaling pathway.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eHepatocyte-Specific Transcription Factors\u003c/strong\u003e \u003cp\u003eHNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, and SOX9 are critical regulators of hepatocyte differentiation and function. Dysregulation of these transcription factors disrupts the genetic programing of hepatocytes, leading to the emergence of heterogeneous cell populations within HCC tumors. For instance, downregulation of HNF4A and HNF1A has been associated with loss of hepatocyte identity and acquisition of progenitor-like traits in HCC cells. Similarly, aberrant expression of FOXA1/2, CEBPA, GATA4/6, PROX1, and SOX9 contributes to phenotypic diversity and transdifferentiation events in HCC.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eSignaling Pathways\u003c/strong\u003e \u003cp\u003eActivation of NOTCH, Wnt/β-catenin, FGF, HGF, TGF-β, and Hippo signaling pathways plays key roles in HCC heterogeneity and transdifferentiation. NOTCH signaling promotes cellular plasticity and self-renewal capacity in HCC cells, contributing to the maintenance of tumor heterogeneity. Dysregulated Wnt/β-catenin signaling induces EMT and promotes the emergence of cancer stem cells with enhanced tumorigenic potential. FGF and HGF signaling pathways stimulate hepatocyte proliferation and survival, driving the expansion of heterogeneous cell populations within HCC tumors. TGF-β signaling induces EMT and promotes the acquisition of mesenchymal characteristics in HCC cells. Dysregulated Hippo signaling disrupts cell-cell interactions and promotes YAP/TAZ-mediated transdifferentiation events in HCC.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eInterplay of Factors and Pathways\u003c/strong\u003e \u003cp\u003eThe interplay between hepatocyte-specific transcription factors and signaling pathways contributes to the complex landscape of HCC heterogeneity and transdifferentiation. Crosstalk between these factors and pathways modulates cellular plasticity, differentiation state, and therapeutic response in HCC. For example, Hippo signaling regulates the expression of HNF4A and HNF6, thereby influencing hepatocyte differentiation and transdifferentiation events in HCC. Similarly, NOTCH signaling interacts with Wnt/β-catenin and TGF-β pathways to promote EMT and cancer stemness in HCC cells.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eClinical Implications\u003c/strong\u003e \u003cp\u003eThe heterogeneity and transdifferentiation observed in HCC have profound clinical implications for patient management and treatment outcomes. Understanding the molecular mechanisms driving these processes is essential for identifying novel therapeutic targets and developing precision medicine approaches tailored to individual patients. Targeting key transcription factors and signaling pathways involved in HCC heterogeneity and transdifferentiation holds promise for improving therapeutic efficacy and overcoming drug resistance in HCC.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eFuture Directions\u003c/strong\u003e \u003cp\u003eThe emergence of HCC heterogeneity and transdifferentiation is governed by a complex interplay of hepatocyte-specific transcription factors and signaling pathways. Elucidating the molecular mechanisms underlying these processes is essential for advancing our understanding of HCC pathogenesis and developing effective therapeutic strategies. Future research efforts should focus on uncovering the dynamic regulatory networks driving HCC heterogeneity and transdifferentiation, with the ultimate goal of improving patient outcomes in this deadly disease.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eKey Findings\u003c/b\u003e:\u003c/p\u003e \u003cp\u003eDysregulation of hepatocyte-specific genes and signaling pathways contributes to the emergence of heterogeneity and transdifferentiation in hepatocellular carcinoma (HCC). Key transcription factors such as HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, HNF6/Onecut1, and ONECUT2/HNF6β are dysregulated in HCC, disrupting hepatocyte genetic programming. Signaling pathways including the Wnt/β-catenin pathway, fibroblast growth factor (FGF) signaling, hepatocyte growth factor (HGF) signaling, transforming growth factor-beta (TGF-β) signaling, and the Hippo signaling pathway are dysregulated in HCC, influencing cellular fate decisions and promoting stemness. Dysregulation of NOTCH signaling components and TBX3/18 transcription factors further complicates the heterogeneity observed in HCC tumors. Investigating the dysregulated expression of hepatocyte-specific genes, transcription factors, and signaling pathways provides insights for targeted therapeutic interventions aimed at disrupting these pathways and improving patient outcomes in HCC.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe decline in the gene expression of hepatocyte cell type-specific genes dysregulates the genetic programming of hepatocytes involved in cell type-specific homeostasis. This fundamental disruption sets the stage for the emergence of heterogeneity within hepatocellular carcinoma (HCC). Through our investigation into the expression patterns of hepatocyte genes, transcription factors (TFs), and signaling pathways across different cell types and tumors, we have gained critical insights into the underlying mechanisms driving this heterogeneity and transdifferentiation in HCC. The dysregulation of hepatocyte-specific genes such as HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, and others serves as a cornerstone for the cellular plasticity observed in HCC. These genes, which play roles in hepatocyte development and homeostasis, are essential for maintaining cellular identity and function. However, their aberrant expression in HCC disrupts the delicate balance of hepatocyte-specific gene expression patterns, leading to The emergence of heterogeneous cell populations within the tumor.\u003c/p\u003e \u003cp\u003ethe dysregulated expression of key signaling pathways, including the Wnt/β-catenin pathway, FGF signaling, HGF signaling, TGF-β signaling, and the Hippo signaling pathway, further contributes to the phenotypic diversity and therapeutic resistance observed in HCC. Activation or inhibition of these pathways influences cellular behavior and modulates the tumor microenvironment, creating a complex landscape of heterogeneous cell populations with distinct molecular profiles and functional characteristics. The dysregulation of hepatocyte-specific genes and signaling pathways serves as a catalyst for the emergence of heterogeneity and transdifferentiation in HCC.\u003c/p\u003e \u003cp\u003eThe implications of our investigation extend beyond a mere understanding of HCC heterogeneity. By elucidating the molecular mechanisms driving cellular plasticity and transdifferentiation in HCC, we have laid the groundwork for the development of targeted therapeutic strategies aimed at disrupting these pathways and improving patient outcomes. Targeted inhibition of key transcription factors or signaling pathways implicated in HCC heterogeneity holds promise for overcoming therapeutic resistance and improving the efficacy of existing treatment modalities. Moreover, our findings underscore the importance of personalized medicine approaches in HCC management. The heterogeneity observed in HCC tumors necessitates tailored therapeutic interventions that account for the diverse molecular profiles and cellular phenotypes within individual tumors. By deciphering the molecular underpinnings of HCC heterogeneity, we can identify novel biomarkers for patient stratification and develop precision medicine strategies that target specific molecular vulnerabilities in HCC tumors.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eHCC: Hepatocellular carcinoma \u003c/p\u003e\n\u003cp\u003eTFs: Transcription factors \u003c/p\u003e\n\u003cp\u003eFGF: Fibroblast growth factor \u003c/p\u003e\n\u003cp\u003eHGF: Hepatocyte growth factor \u003c/p\u003e\n\u003cp\u003eTGF-\u0026beta;: Transforming growth factor-beta \u003c/p\u003e\n\u003cp\u003eWnt: Wingless-related integration site \u003c/p\u003e\n\u003cp\u003eNOTCH: Neurogenic locus notch homolog protein \u003c/p\u003e\n\u003cp\u003eHippo: Hippo signaling pathway \u003c/p\u003e\n\u003cp\u003eHNF4A: Hepatocyte nuclear factor 4 alpha \u003c/p\u003e\n\u003cp\u003eHNF1A: Hepatocyte nuclear factor 1 alpha \u003c/p\u003e\n\u003cp\u003eFOXA1/2: Forkhead box protein A1/2 \u003c/p\u003e\n\u003cp\u003eCEBPA: CCAAT/enhancer-binding protein alpha \u003c/p\u003e\n\u003cp\u003eGATA4/6: GATA binding protein 4/6 \u003c/p\u003e\n\u003cp\u003ePROX1: Prospero homeobox protein 1 \u003c/p\u003e\n\u003cp\u003eSOX9: SRY-box transcription factor 9 \u003c/p\u003e\n\u003cp\u003eHNF6/Onecut1: Hepatocyte nuclear factor 6/Onecut homeobox 1 \u003c/p\u003e\n\u003cp\u003eONECUT2/HNF6\u0026beta;: Onecut homeobox 2/Hepatocyte nuclear factor 6 beta \u003c/p\u003e\n\u003cp\u003eTBX3/18: T-box transcription factor 3/18 \u003c/p\u003e\n\u003cp\u003emiRNA: MicroRNA \u003c/p\u003e\n\u003cp\u003eERK: Extracellular signal-regulated kinase \u003c/p\u003e\n\u003cp\u003eMAPK: Mitogen-activated protein kinase PI3K: Phosphoinositide 3-kinase \u003c/p\u003e\n\u003cp\u003eAKT: Protein kinase B STAT3: Signal transducer and activator of transcription 3 \u003c/p\u003e\n\u003cp\u003eEGFR: Epidermal growth factor receptor \u003c/p\u003e\n\u003cp\u003eIGF: Insulin-like growth factor \u003c/p\u003e\n\u003cp\u003eHIF: Hypoxia-inducible factor \u003c/p\u003e\n\u003cp\u003eVEGF: Vascular endothelial growth factor \u003c/p\u003e\n\u003cp\u003eECM: Extracellular matrix \u003c/p\u003e\n\u003cp\u003eROS: Reactive oxygen species \u003c/p\u003e\n\u003cp\u003eJAK: Janus kinase \u003c/p\u003e\n\u003cp\u003eNF-\u0026kappa;B: Nuclear factor kappa-light-chain-enhancer of activated B cells\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics declarations:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability statement:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI declare that there was not any source of funding for this research work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026ldquo;Not applicable\u0026rdquo;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contribution: \u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\n\u003cp\u003e\u003cstrong\u003eOvais Shafi (OS)*\u003c/strong\u003e is the author of the study and was involved in the idea, concept, design, and methodology of the study, literature search and references. He did the writing, editing, and revision of the manuscript. He was involved in drawing the findings, results, conclusions, implications of the study, interpretation of the data and was involved in all aspects of the study. He prepared and wrote discussion, results, conclusions and all areas of the study. OS extracted and analyzed the data. He was involved in critical evaluation, audit of every aspect of the study, data extraction, adherence of the study to relevant PRISMA guidelines, limitations of the study, references, and all others. He was involved in drawing fig 1. The author read and approved the manuscript.\u003c/p\u003e\n\u003cp\u003eHe investigated hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6\u0026beta;, TBX3/18, Wnt/\u0026beta;-catenin pathway, FGF, HGF, TGF-\u0026beta;, Hippo signaling pathway.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOvais Shafi (OS)*\u003c/strong\u003e, MBBS - Sindh Medical College - Dow University of Health Sciences, Karachi, Pakistan. He aspires to become an eminent \u0026lsquo;Physician Scientist\u0026rsquo;. He is devoted to the research in disease development mechanisms, disease origins and therapeutics. OS is also passionate about multiple research areas including clinical trials, clinical medicine, therapeutics, regenerative medicine, precision medicine including gene therapies, finding disease specific targets for gene therapy, role of disease genomics and epigenetics in diagnosis, management, and therapeutics development. He is dedicated to the field of research and clinical medicine.\u003c/p\u003e\n\u003cp\u003eEmail address*: \u003ca href=\"mailto:[email protected]\"\[email protected]\u003c/a\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding author: OS \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to \u003ca href=\"mailto:[email protected]\"\u003eOvais Shafi\u003c/a\u003e\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003e\u003cstrong\u003eRahimeen Rajpar (RR) \u003c/strong\u003eis also the author of the study and contributed to the writing, editing and revision of the study. She also contributed to the results and conclusions of this manuscript along with working on the findings.\u003c/p\u003e\n\u003cp\u003eShe contributed to investigating the hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6\u0026beta;, TBX3/18, Wnt/\u0026beta;-catenin pathway, FGF, HGF, TGF-\u0026beta;, Hippo signaling pathway.\u003c/p\u003e\n\u003cp\u003eRahimeen Rajpar, MD is a dedicated medical professional with a passion for unraveling the mysteries of disease origins and progression. Currently pursuing her residency in internal medicine, RR harbors ambitions of specializing in oncology, with a focus on understanding and treating various forms of cancer. RR's commitment to advancing medical knowledge extends beyond the laboratory, she is working towards becoming a leader in the world of Medicine and Oncology, looking at the medical intricacies from a different lens. Apart from research RR remains dedicated to improving the lives of her patients through comprehensive care and by working towards scientific discoveries.\u003c/p\u003e\n\u003cp\u003eRR is a MBBS graduate from Sindh Medical College \u0026ndash; Jinnah Sindh Medical University, Karachi, Pakistan.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003e\u003cstrong\u003eShakaib Zafar (SZ)\u003c/strong\u003e is the co-author of the study. He contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections along with working on references. He contributed to investigating the hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6\u0026beta;, TBX3/18, Wnt/\u0026beta;-catenin pathway, FGF, HGF, TGF-\u0026beta;, Hippo signaling pathway.\u003c/p\u003e\n\u003cp\u003eDr Shakaib Zafar, MBBS - Sindh Medical College - Dow University of Health Sciences, Karachi, Pakistan. He is currently working at Aga khan University Hospital, after the completion of residency in Anaesthesiology. Areas of Research Interest include disease develop mechanisms and disease origins which are the pillars of the field of Medicine.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003e\u003cstrong\u003eSaba Irfan (SI)\u003c/strong\u003e is the co-author of the study. She contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections along with working on references. She contributed to investigating the hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6\u0026beta;, TBX3/18, Wnt/\u0026beta;-catenin pathway, FGF, HGF, TGF-\u0026beta;, Hippo signaling pathway.\u003c/p\u003e\n\u003cp\u003eSaba Irfan MBBS, MD from Columbus, Ohio is an accomplished physician who graduated from Federal Medical and Dental College, Pakistan with extensive clinical experience across Pakistan, Canada, and the USA. Her interests lie in research studies, value-based medicine, and quality improvement initiatives. Currently pursuing a research fellowship affiliated with Michigan State University.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003e\u003cstrong\u003eMuhammad Ashar (MA)\u003c/strong\u003e is the co-author of the study. He contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections along with working on references. He contributed to investigating the hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6\u0026beta;, TBX3/18, Wnt/\u0026beta;-catenin pathway, FGF, HGF, TGF-\u0026beta;, Hippo signaling pathway.\u003c/p\u003e\n\u003cp\u003eMuhammad Ashar, MD is a Resident Medical Officer in the Department of General Surgery at Aga Khan University Hospital, Karachi, Pakistan. His research focuses on hepatocellular carcinoma and other gastrointestinal malignancies. He is ECFMG certified and holds a medical license in the United States, with plans to pursue further training and a career in surgical oncology in the US. His research interests include: hepato-pancreato-biliary cancers, gastrointestinal oncology, esophageal cancers, and is currently affiliated with Aga Khan University Hospital, Department of General Surgery, Hepato-Pancreato-Biliary and Surgical Oncology, Karachi, Pakistan.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003e\u003cstrong\u003eShah Hussain Jafry (SHJ)\u003c/strong\u003e is the co-author of the study. He contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections along with working on references. He contributed to investigating the hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6\u0026beta;, TBX3/18, Wnt/\u0026beta;-catenin pathway, FGF, HGF, TGF-\u0026beta;, Hippo signaling pathway.\u003c/p\u003e\n\u003cp\u003eShah Hussain Jafry, MBBS - Sindh Medical College \u0026ndash; Jinnah Sindh Medical University, Karachi, Pakistan. He graduated in 2021 with the hopes of matching in Internal Medicine. He has completed both USMLE Step 1 and 2, and plans to participate in the upcoming match season 2024/25. Areas of research interest include disease development mechanisms and disease origins which are the pillars of the field of medicine.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003e\u003cstrong\u003eLuqman Naseer Virk (LNV)\u003c/strong\u003e is the co-author of the study. He contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections along with working on references. He contributed to investigating the hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6\u0026beta;, TBX3/18, Wnt/\u0026beta;-catenin pathway, FGF, HGF, TGF-\u0026beta;, Hippo signaling pathway.\u003c/p\u003e\n\u003cp\u003eLuqman Naseer Virk, MBBS - Sindh Medical College - Dow University of Health Sciences, Karachi, Pakistan. He is a vibrant and talented researcher. Areas of research interest include disease development mechanisms and disease origins which are the pillars of the field of medicine.\u003c/p\u003e\n\u003c/li\u003e\n\u003cli\u003e\n\u003cp\u003e\u003cstrong\u003eRaveena (RA)\u003c/strong\u003e is the co-author of the study. She contributed to the results and conclusions of the study, also contributed to the writing and editing of these sections along with working on references. She contributed to investigating the hepatocyte-specific genes/ signaling pathways/ TFs for their roles in relation to this study: HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, NOTCH, HNF6/ Onecut1, ONECUT2/ HNF6\u0026beta;, TBX3/18, Wnt/\u0026beta;-catenin pathway, FGF, HGF, TGF-\u0026beta;, Hippo signaling pathway.\u003c/p\u003e\n\u003cp\u003eRaveena, MBBS - Sindh Medical College \u0026ndash; Jinnah Sindh Medical University, Karachi, Pakistan. She is passionate about research in surgery and disease development mechanisms including neurodegenerative diseases, oncogenesis and others. She is ECFMG Certified. She is passionate about residency in Internal Medicine/Surgery. Her goal is to make significant impact in the field of Research.\u003c/p\u003e\n\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cem\u003eThe work and contributions of everyone have been described in detail, the order is randomized and the numbering is just for referencing purpose. \u003c/em\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBalogh J, Victor D 3rd, Asham EH, Burroughs SG, Boktour M, Saharia A, Li X, Ghobrial RM, Monsour HP Jr. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma. 2016 Oct 5;3:41-53. doi: 10.2147/JHC.S61146. PMID: 27785449; PMCID: PMC5063561.\u003c/li\u003e\n\u003cli\u003eLlovet JM, Kelley RK, Villanueva A, Singal AG, Pikarsky E, Roayaie S, Lencioni R, Koike K, Zucman-Rossi J, Finn RS. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021 Jan 21;7(1):6. doi: 10.1038/s41572-020-00240-3. Erratum in: Nat Rev Dis Primers. 2024 Feb 12;10(1):10. PMID: 33479224.\u003c/li\u003e\n\u003cli\u003eVogel A, Meyer T, Sapisochin G, Salem R, Saborowski A. Hepatocellular carcinoma. Lancet. 2022 Oct 15;400(10360):1345-1362. doi: 10.1016/S0140-6736(22)01200-4. Epub 2022 Sep 6. PMID: 36084663.\u003c/li\u003e\n\u003cli\u003eSchulze RJ, Schott MB, Casey CA, Tuma PL, McNiven MA. The cell biology of the hepatocyte: A membrane trafficking machine. J Cell Biol. 2019 Jul 1;218(7):2096-2112. doi: 10.1083/jcb.201903090. Epub 2019 Jun 14. PMID: 31201265; PMCID: PMC6605791.\u003c/li\u003e\n\u003cli\u003eShin D, Monga SP. Cellular and molecular basis of liver development. Compr Physiol. 2013 Apr;3(2):799-815. doi: 10.1002/cphy.c120022. PMID: 23720330; PMCID: PMC4445238.\u003c/li\u003e\n\u003cli\u003eOber EA, Lemaigre FP. Development of the liver: Insights into organ and tissue morphogenesis. J Hepatol. 2018 May;68(5):1049-1062. doi: 10.1016/j.jhep.2018.01.005. Epub 2018 Jan 13. PMID: 29339113.\u003c/li\u003e\n\u003cli\u003eSuresh A, Dhanasekaran R. Implications of genetic heterogeneity in hepatocellular cancer. Adv Cancer Res. 2022;156:103-135. doi: 10.1016/bs.acr.2022.01.007. Epub 2022 Mar 7. PMID: 35961697; PMCID: PMC10321863.\u003c/li\u003e\n\u003cli\u003eLu LC, Hsu CH, Hsu C, Cheng AL. Tumor Heterogeneity in Hepatocellular Carcinoma: Facing the Challenges. Liver Cancer. 2016 Apr;5(2):128-38. doi: 10.1159/000367754. Epub 2016 Mar 17. PMID: 27386431; PMCID: PMC4906428.\u003c/li\u003e\n\u003cli\u003eKalasekar SM, VanSant-Webb CH, Evason KJ. Intratumor Heterogeneity in Hepatocellular Carcinoma: Challenges and Opportunities. Cancers (Basel). 2021 Nov 3;13(21):5524. doi: 10.3390/cancers13215524. PMID: 34771685; PMCID: PMC8582820.\u003c/li\u003e\n\u003cli\u003eFriemel J, Rechsteiner M, Frick L, B\u0026ouml;hm F, Struckmann K, Egger M, Moch H, Heikenwalder M, Weber A. Intratumor heterogeneity in hepatocellular carcinoma. Clin Cancer Res. 2015 Apr 15;21(8):1951-61. doi: 10.1158/1078-0432.CCR-14-0122. Epub 2014 Sep 23. PMID: 25248380.\u003c/li\u003e\n\u003cli\u003eSafri F, Nguyen R, Zerehpooshnesfchi S, George J, Qiao L. Heterogeneity of hepatocellular carcinoma: from mechanisms to clinical implications. Cancer Gene Ther. 2024 Mar 18. doi: 10.1038/s41417-024-00764-w. Epub ahead of print. PMID: 38499648.\u003c/li\u003e\n\u003cli\u003eCabillic F, Corlu A. Regulation of Transdifferentiation and Retrodifferentiation by Inflammatory Cytokines in Hepatocellular Carcinoma. Gastroenterology. 2016 Oct;151(4):607-15. doi: 10.1053/j.gastro.2016.06.052. Epub 2016 Jul 19. PMID: 27443822.\u003c/li\u003e\n\u003cli\u003eCerec V, Glaise D, Garnier D, Morosan S, Turlin B, Drenou B, Gripon P, Kremsdorf D, Guguen-Guillouzo C, Corlu A. Transdifferentiation of hepatocyte-like cells from the human hepatoma HepaRG cell line through bipotent progenitor. Hepatology. 2007 Apr;45(4):957-67. doi: 10.1002/hep.21536. PMID: 17393521.\u003c/li\u003e\n\u003cli\u003eHughes A, Dhoot GK. Dysregulated cancer cell transdifferentiation into erythrocytes is an additional metabolic stress in hepatocellular carcinoma. Tumour Biol. 2018 Nov;40(11):1010428318811467. doi: 10.1177/1010428318811467. PMID: 30419801.\u003c/li\u003e\n\u003cli\u003eShen CN, Slack JM, Tosh D. Molecular basis of transdifferentiation of pancreas to liver. Nat Cell Biol. 2000 Dec;2(12):879-87. doi: 10.1038/35046522. PMID: 11146651.\u003c/li\u003e\n\u003cli\u003eMeindl-Beinker NM, Dooley S. Transforming growth factor-beta and hepatocyte transdifferentiation in liver fibrogenesis. J Gastroenterol Hepatol. 2008 Mar;23 Suppl 1:S122-7. doi: 10.1111/j.1440-1746.2007.05297.x. PMID: 18336655.\u003c/li\u003e\n\u003cli\u003eDeLaForest A, Nagaoka M, Si-Tayeb K, Noto FK, Konopka G, Battle MA, Duncan SA. HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells. Development. 2011 Oct;138(19):4143-53. doi: 10.1242/dev.062547. Epub 2011 Aug 18. PMID: 21852396; PMCID: PMC3171218.\u003c/li\u003e\n\u003cli\u003eParviz F, Matullo C, Garrison WD, Savatski L, Adamson JW, Ning G, Kaestner KH, Rossi JM, Zaret KS, Duncan SA. Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet. 2003 Jul;34(3):292-6. doi: 10.1038/ng1175. PMID: 12808453.\u003c/li\u003e\n\u003cli\u003eMarable SS, Chung E, Park JS. Hnf4a Is Required for the Development of Cdh6-Expressing Progenitors into Proximal Tubules in the Mouse Kidney. J Am Soc Nephrol. 2020 Nov;31(11):2543-2558. doi: 10.1681/ASN.2020020184. Epub 2020 Aug 6. PMID: 32764140; PMCID: PMC7608976.\u003c/li\u003e\n\u003cli\u003eYoshimura Y, Muto Y, Omachi K, Miner JH, Humphreys BD. Elucidating the Proximal Tubule HNF4A Gene Regulatory Network in Human Kidney Organoids. J Am Soc Nephrol. 2023 Oct 1;34(10):1672-1686. doi: 10.1681/ASN.0000000000000197. Epub 2023 Jul 25. PMID: 37488681; PMCID: PMC10561821.\u003c/li\u003e\n\u003cli\u003eChen L, Toke NH, Luo S, Vasoya RP, Aita R, Parthasarathy A, Tsai YH, Spence JR, Verzi MP. HNF4 factors control chromatin accessibility and are redundantly required for maturation of the fetal intestine. Development. 2019 Aug 6;146(19):dev179432. doi: 10.1242/dev.179432. PMID: 31345929; PMCID: PMC6803367.\u003c/li\u003e\n\u003cli\u003eKaci A, Solheim MH, Silgjerd T, Hjaltadottir J, Hornnes LH, Molnes J, Madsen A, Sj\u0026oslash;holt G, Bellann\u0026eacute;-Chantelot C, Caswell R, Sagen JV, Nj\u0026oslash;lstad PR, Aukrust I, Bj\u0026oslash;rkhaug L. Functional characterization of HNF4A gene variants identify promoter and cell line specific transactivation effects. Hum Mol Genet. 2024 Mar 3:ddae027. doi: 10.1093/hmg/ddae027. Epub ahead of print. PMID: 38433330.\u003c/li\u003e\n\u003cli\u003eLei X, Ketelut-Carneiro N, Shmuel-Galia L, Xu W, Wilson R, Vierbuchen T, Chen Y, Reboldi A, Kang J, Edelblum KL, Ward D, Fitzgerald KA. Epithelial HNF4A shapes the intraepithelial lymphocyte compartment via direct regulation of immune signaling molecules. J Exp Med. 2022 Aug 1;219(8):e20212563. doi: 10.1084/jem.20212563. Epub 2022 Jul 6. PMID: 35792863; PMCID: PMC9263552.\u003c/li\u003e\n\u003cli\u003eMichelson DA, Zuo C, Verzi M, Benoist C, Mathis D. Hnf4 activates mimetic-cell enhancers to recapitulate gut and liver development within the thymus. J Exp Med. 2023 Oct 2;220(10):e20230461. doi: 10.1084/jem.20230461. Epub 2023 Jul 3. PMID: 37399024; PMCID: PMC10318407.\u003c/li\u003e\n\u003cli\u003eDubois V, Staels B, Lefebvre P, Verzi MP, Eeckhoute J. Control of Cell Identity by the Nuclear Receptor HNF4 in Organ Pathophysiology. Cells. 2020 Sep 28;9(10):2185. doi: 10.3390/cells9102185. PMID: 32998360; PMCID: PMC7600215.\u003c/li\u003e\n\u003cli\u003eMa HM, Zhang Q, Yang XM, Hu Y, Zhang J, Chen L, Zhao B, Yang WT, Xu R. HNF4A Regulates the Proliferation and Tumor Formation of Cervical Cancer Cells through the Wnt/\u003cem\u003e\u0026beta;\u003c/em\u003e-Catenin Pathway. Oxid Med Cell Longev. 2022 Jan 28;2022:8168988. doi: 10.1155/2022/8168988. PMID: 35132353; PMCID: PMC8817108.\u003c/li\u003e\n\u003cli\u003eVuong LM, Chellappa K, Dhahbi JM, Deans JR, Fang B, Bolotin E, Titova NV, Hoverter NP, Spindler SR, Waterman ML, Sladek FM. Differential Effects of Hepatocyte Nuclear Factor 4\u0026alpha; Isoforms on Tumor Growth and T-Cell Factor 4/AP-1 Interactions in Human Colorectal Cancer Cells. Mol Cell Biol. 2015 Oct;35(20):3471-90. doi: 10.1128/MCB.00030-15. Epub 2015 Aug 3. PMID: 26240283; PMCID: PMC4573706.\u003c/li\u003e\n\u003cli\u003eSugai M, Umezu H, Yamamoto T, Jiang S, Iwanari H, Tanaka T, Hamakubo T, Kodama T, Naito M. Expression of hepatocyte nuclear factor 4 alpha in primary ovarian mucinous tumors. Pathol Int. 2008 Nov;58(11):681-6. doi: 10.1111/j.1440-1827.2008.02293.x. PMID: 18844932.\u003c/li\u003e\n\u003cli\u003eMa HM, Zhang Q, Yang XM, Hu Y, Zhang J, Chen L, Zhao B, Yang WT, Xu R. HNF4A Regulates the Proliferation and Tumor Formation of Cervical Cancer Cells through the Wnt/\u003cem\u003e\u0026beta;\u003c/em\u003e-Catenin Pathway. Oxid Med Cell Longev. 2022 Jan 28;2022:8168988. doi: 10.1155/2022/8168988. PMID: 35132353; PMCID: PMC8817108.\u003c/li\u003e\n\u003cli\u003eWang Z, Li Y, Wu D, Yu S, Wang Y, Leung Chan F. Nuclear receptor HNF4\u0026alpha; performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence. Oncogene. 2020 Feb;39(7):1572-1589. doi: 10.1038/s41388-019-1080-3. Epub 2019 Nov 6. Erratum in: Oncogene. 2020 Sep;39(39):6263. PMID: 31695151; PMCID: PMC7018660.\u003c/li\u003e\n\u003cli\u003eNing BF, Ding J, Yin C, Zhong W, Wu K, Zeng X, Yang W, Chen YX, Zhang JP, Zhang X, Wang HY, Xie WF. Hepatocyte nuclear factor 4 alpha suppresses the development of hepatocellular carcinoma. Cancer Res. 2010 Oct 1;70(19):7640-51. doi: 10.1158/0008-5472.CAN-10-0824. Epub 2010 Sep 28. PMID: 20876809.\u003c/li\u003e\n\u003cli\u003eShokouhian B, Negahdari B, Heydari Z, Totonchi M, Aboulkheyr Es H, Piryaei A, Mostafavi E, Vosough M. HNF4\u0026alpha; is possibly the missing link between epithelial-mesenchymal transition and Warburg effect during hepatocarcinogenesis. Cancer Sci. 2023 Apr;114(4):1337-1352. doi: 10.1111/cas.15686. Epub 2022 Dec 19. PMID: 36479791; PMCID: PMC10067433.\u003c/li\u003e\n\u003cli\u003eSuresh A, Dhanasekaran R. Implications of genetic heterogeneity in hepatocellular cancer. Adv Cancer Res. 2022;156:103-135. doi: 10.1016/bs.acr.2022.01.007. Epub 2022 Mar 7. PMID: 35961697; PMCID: PMC10321863.\u003c/li\u003e\n\u003cli\u003eSang L, Wang X, Bai W, Shen J, Zeng Y, Sun J. The role of hepatocyte nuclear factor\u0026thinsp;4\u0026alpha;\u0026thinsp;(HNF4\u0026alpha;)\u0026thinsp;in\u0026thinsp;tumorigenesis. Front Oncol. 2022 Sep 28;12:1011230. doi: 10.3389/fonc.2022.1011230. PMID: 36249028; PMCID: PMC9554155.\u003c/li\u003e\n\u003cli\u003eXu L, Hui L, Wang S, Gong J, Jin Y, Wang Y, Ji Y, Wu X, Han Z, Hu G. Expression profiling suggested a regulatory role of liver-enriched transcription factors in human hepatocellular carcinoma. Cancer Res. 2001 Apr 1;61(7):3176-81. PMID: 11306505.\u003c/li\u003e\n\u003cli\u003eD\u0026eacute;sert R, Nieto N, Musso O. Dimensions of hepatocellular carcinoma phenotypic diversity. World J Gastroenterol. 2018 Oct 28;24(40):4536-4547. doi: 10.3748/wjg.v24.i40.4536. PMID: 30386103; PMCID: PMC6209578.\u003c/li\u003e\n\u003cli\u003eMiyachi Y, Miyazawa T, Ogawa Y. HNF1A Mutations and Beta Cell Dysfunction in Diabetes. Int J Mol Sci. 2022 Mar 16;23(6):3222. doi: 10.3390/ijms23063222. PMID: 35328643; PMCID: PMC8948720.\u003c/li\u003e\n\u003cli\u003eLi LM, Jiang BG, Sun LL. HNF1A：From Monogenic Diabetes to Type 2 Diabetes and Gestational Diabetes Mellitus. Front Endocrinol (Lausanne). 2022 Mar 1;13:829565. doi: 10.3389/fendo.2022.829565. PMID: 35299962; PMCID: PMC8921476.\u003c/li\u003e\n\u003cli\u003eQian MF, Bevacqua RJ, Coykendall VM, Liu X, Zhao W, Chang CA, Gu X, Dai XQ, MacDonald PE, Kim SK. HNF1\u0026alpha; maintains pancreatic \u0026alpha; and \u0026beta; cell functions in primary human islets. JCI Insight. 2023 Dec 22;8(24):e170884. doi: 10.1172/jci.insight.170884. PMID: 37943614; PMCID: PMC10807710.\u003c/li\u003e\n\u003cli\u003eKavitha B, Ranganathan S, Gopi S, Vetrivel U, Hemavathy N, Mohan V, Radha V. Molecular characterization and re-interpretation of \u003cem\u003eHNF1A\u003c/em\u003e variants identified in Indian MODY subjects towards precision medicine. Front Endocrinol (Lausanne). 2023 Jun 16;14:1177268. doi: 10.3389/fendo.2023.1177268. PMID: 37396188; PMCID: PMC10313120.\u003c/li\u003e\n\u003cli\u003eSepehri Z, Banerjee A, Vizeacoumar FS, Freywald A, Vizeacoumar FJ, Dolinsky VW, Davie JR. Differential expression of HNF1A and HNF1A-AS1 in colon cancer cells. IUBMB Life. 2022 Jun;74(6):496-507. doi: 10.1002/iub.2609. Epub 2022 Mar 2. PMID: 35184384.\u003c/li\u003e\n\u003cli\u003eDeForest N, Kavitha B, Hu S, Isaac R, Krohn L, Wang M, Du X, De Arruda Saldanha C, Gylys J, Merli E, Abagyan R, Najmi L, Mohan V; Alnylam Human Genetics; AMP-T2D Consortium; Flannick J, Peloso GM, Gordts PLSM, Heinz S, Deaton AM, Khera AV, Olefsky J, Radha V, Majithia AR. Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of atherogenic lipoproteins. Cell Genom. 2023 May 30;3(7):100339. doi: 10.1016/j.xgen.2023.100339. PMID: 37492105; PMCID: PMC10363808.\u003c/li\u003e\n\u003cli\u003eNajmi LA, Aukrust I, Flannick J, Molnes J, Burtt N, Molven A, Groop L, Altshuler D, Johansson S, Bj\u0026oslash;rkhaug L, Nj\u0026oslash;lstad PR. Functional Investigations of HNF1A Identify Rare Variants as Risk Factors for Type 2 Diabetes in the General Population. Diabetes. 2017 Feb;66(2):335-346. doi: 10.2337/db16-0460. Epub 2016 Nov 29. PMID: 27899486; PMCID: PMC5860263.\u003c/li\u003e\n\u003cli\u003eLuo Z, Li Y, Wang H, Fleming J, Li M, Kang Y, Zhang R, Li D. Hepatocyte nuclear factor 1A (HNF1A) as a possible tumor suppressor in pancreatic cancer. PLoS One. 2015 Mar 20;10(3):e0121082. doi: 10.1371/journal.pone.0121082. PMID: 25793983; PMCID: PMC4368635.\u003c/li\u003e\n\u003cli\u003eLiu Y, Zhao F, Tan F, Tang L, Du Z, Mou J, Zhou G, Yuan C. HNF1A-AS1: A Tumor-associated Long Non-coding RNA. Curr Pharm Des. 2022;28(21):1720-1729. doi: 10.2174/1381612828666220520113846. PMID: 35619319.\u003c/li\u003e\n\u003cli\u003eCai C, Bi D, Bick G, Wei Q, Liu H, Lu L, Zhang X, Qin H. Hepatocyte nuclear factor HNF1A is a potential regulator in shaping the super-enhancer landscape in colorectal cancer liver metastasis. FEBS Lett. 2021 Dec;595(24):3056-3071. doi: 10.1002/1873-3468.14219. Epub 2021 Nov 22. PMID: 34719039.\u003c/li\u003e\n\u003cli\u003eAbel EV, Goto M, Magnuson B, Abraham S, Ramanathan N, Hotaling E, Alaniz AA, Kumar-Sinha C, Dziubinski ML, Urs S, Wang L, Shi J, Waghray M, Ljungman M, Crawford HC, Simeone DM. HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties. Elife. 2018 Aug 3;7:e33947. doi: 10.7554/eLife.33947. PMID: 30074477; PMCID: PMC6122955.\u003c/li\u003e\n\u003cli\u003eFujino S, Miyoshi N, Ito A, Yasui M, Matsuda C, Ohue M, Uemura M, Mizushima T, Doki Y, Eguchi H. HNF1A regulates colorectal cancer progression and drug resistance as a downstream of POU5F1. Sci Rep. 2021 May 14;11(1):10363. doi: 10.1038/s41598-021-89126-2. PMID: 33990627; PMCID: PMC8121855.\u003c/li\u003e\n\u003cli\u003eSchulze K, Zucman-Rossi J. Current issues on genomic heterogeneity in hepatocellular carcinoma and its implication in clinical practice. Hepat Oncol. 2015 Jul;2(3):291-302. doi: 10.2217/hep.15.16. Epub 2015 Jul 27. PMID: 30191009; PMCID: PMC6095162.\u003c/li\u003e\n\u003cli\u003eJin K, Lan H, Wang X, Lv J. Genetic heterogeneity in hepatocellular carcinoma and paired bone metastasis revealed by next-generation sequencing. Int J Clin Exp Pathol. 2017 Oct 1;10(10):10495-10504. PMID: 31966388; PMCID: PMC6965764.\u003c/li\u003e\n\u003cli\u003eMcGlacken-Byrne SM, Mohammad JK, Conlon N, Gubaeva D, Siersb\u0026aelig;k J, Schou AJ, Demirbilek H, Dastamani A, Houghton JAL, Brusgaard K, Melikyan M, Christesen H, Flanagan SE, Murphy NP, Shah P. Clinical and genetic heterogeneity of HNF4A/HNF1A mutations in a multicentre paediatric cohort with hyperinsulinaemic hypoglycaemia. Eur J Endocrinol. 2022 Feb 22;186(4):417-427. doi: 10.1530/EJE-21-0897. PMID: 35089870.\u003c/li\u003e\n\u003cli\u003eHechtman JF, Abou-Alfa GK, Stadler ZK, Mandelker DL, Roehrl MHA, Zehir A, Vakiani E, Middha S, Klimstra DS, Shia J. Somatic HNF1A mutations in the malignant transformation of hepatocellular adenomas: a retrospective analysis of data from MSK-IMPACT and TCGA. Hum Pathol. 2019 Jan;83:1-6. doi: 10.1016/j.humpath.2018.08.004. Epub 2018 Aug 17. PMID: 30121369; PMCID: PMC6365190.\u003c/li\u003e\n\u003cli\u003eBarcena-Varela M, Lujambio A. The Endless Sources of Hepatocellular Carcinoma Heterogeneity. Cancers (Basel). 2021 May 26;13(11):2621. doi: 10.3390/cancers13112621. PMID: 34073538; PMCID: PMC8198457.\u003c/li\u003e\n\u003cli\u003eFriedman JR, Kaestner KH. The Foxa family of transcription factors in development and metabolism. Cell Mol Life Sci. 2006 Oct;63(19-20):2317-28. doi: 10.1007/s00018-006-6095-6. PMID: 16909212.\u003c/li\u003e\n\u003cli\u003eGeusz RJ, Wang A, Lam DK, Vinckier NK, Alysandratos KD, Roberts DA, Wang J, Kefalopoulou S, Ramirez A, Qiu Y, Chiou J, Gaulton KJ, Ren B, Kotton DN, Sander M. Sequence logic at enhancers governs a dual mechanism of endodermal organ fate induction by FOXA pioneer factors. Nat Commun. 2021 Nov 17;12(1):6636. doi: 10.1038/s41467-021-26950-0. PMID: 34789735; PMCID: PMC8599738.\u003c/li\u003e\n\u003cli\u003eLan Q, Cao M, Kollipara RK, Rosa JB, Kittler R, Jiang H. FoxA transcription factor Fork head maintains the intestinal stem/progenitor cell identities in Drosophila. Dev Biol. 2018 Jan 15;433(2):324-343. doi: 10.1016/j.ydbio.2017.09.002. Epub 2017 Nov 3. PMID: 29108672.\u003c/li\u003e\n\u003cli\u003eHeslop JA, Duncan SA. FoxA factors: the chromatin key and doorstop essential for liver development and function. Genes Dev. 2020 Aug 1;34(15-16):1003-1004. doi: 10.1101/gad.340570.120. PMID: 32747476; PMCID: PMC7397850.\u003c/li\u003e\n\u003cli\u003eFournier M, Bourriquen G, Lamaze FC, C\u0026ocirc;t\u0026eacute; MC, Fournier \u0026Eacute;, Joly-Beauparlant C, Caron V, Gobeil S, Droit A, Bilodeau S. FOXA and master transcription factors recruit Mediator and Cohesin to the core transcriptional regulatory circuitry of cancer cells. Sci Rep. 2016 Oct 14;6:34962. doi: 10.1038/srep34962. PMID: 27739523; PMCID: PMC5064413.\u003c/li\u003e\n\u003cli\u003eHuang C, Liu J, Xiong B, Yonemura Y, Yang X. Expression and prognosis analyses of forkhead box A (FOXA) family in human lung cancer. Gene. 2019 Feb 15;685:202-210. doi: 10.1016/j.gene.2018.11.022. Epub 2018 Nov 9. PMID: 30415009.\u003c/li\u003e\n\u003cli\u003eMirosevich J, Gao N, Gupta A, Shappell SB, Jove R, Matusik RJ. Expression and role of Foxa proteins in prostate cancer. Prostate. 2006 Jul 1;66(10):1013-28. doi: 10.1002/pros.20299. PMID: 16001449.\u003c/li\u003e\n\u003cli\u003eArruabarrena-Aristorena A, Maag JLV, Kittane S, Cai Y, Karthaus WR, Ladewig E, Park J, Kannan S, Ferrando L, Cocco E, Ho SY, Tan DS, Sallaku M, Wu F, Acevedo B, Selenica P, Ross DS, Witkin M, Sawyers CL, Reis-Filho JS, Verma CS, Jauch R, Koche R, Baselga J, Razavi P, Toska E, Scaltriti M. FOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer. Cancer Cell. 2020 Oct 12;38(4):534-550.e9. doi: 10.1016/j.ccell.2020.08.003. Epub 2020 Sep 3. PMID: 32888433; PMCID: PMC8311901.\u003c/li\u003e\n\u003cli\u003eWolf I, Bose S, Williamson EA, Miller CW, Karlan BY, Koeffler HP. FOXA1: Growth inhibitor and a favorable prognostic factor in human breast cancer. Int J Cancer. 2007 Mar 1;120(5):1013-22. doi: 10.1002/ijc.22389. PMID: 17163418.\u003c/li\u003e\n\u003cli\u003eKatoh M, Igarashi M, Fukuda H, Nakagama H, Katoh M. Cancer genetics and genomics of human FOX family genes. Cancer Lett. 2013 Jan 28;328(2):198-206. doi: 10.1016/j.canlet.2012.09.017. Epub 2012 Sep 27. PMID: 23022474.\u003c/li\u003e\n\u003cli\u003eGong Z, Yu J, Yang S, Lai PBS, Chen GG. FOX transcription factor family in hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer. 2020 Aug;1874(1):188376. doi: 10.1016/j.bbcan.2020.188376. Epub 2020 May 11. PMID: 32437734.\u003c/li\u003e\n\u003cli\u003eLi Z, Tuteja G, Schug J, Kaestner KH. Foxa1 and Foxa2 are essential for sexual dimorphism in liver cancer. Cell. 2012 Jan 20;148(1-2):72-83. doi: 10.1016/j.cell.2011.11.026. PMID: 22265403; PMCID: PMC3266536.\u003c/li\u003e\n\u003cli\u003eOuyang X, Feng L, Yao L, Zhang J, Xiao Y, Liu G, Zhang G, Wang Z. A comprehensive analysis of FOX family in HCC and experimental evidence to support the oncogenic role of FOXH1. Aging (Albany NY). 2022 Mar 7;14(5):2268-2286. doi: 10.18632/aging.203934. Epub 2022 Mar 7. PMID: 35255005; PMCID: PMC8954963.\u003c/li\u003e\n\u003cli\u003eKeng VW, Largaespada DA, Villanueva A. Why men are at higher risk for hepatocellular carcinoma? J Hepatol. 2012 Aug;57(2):453-4. doi: 10.1016/j.jhep.2012.03.004. Epub 2012 Mar 13. PMID: 22425699; PMCID: PMC3506003.\u003c/li\u003e\n\u003cli\u003eZhao Y, Li Z. Interplay of estrogen receptors and FOXA factors in the liver cancer. Mol Cell Endocrinol. 2015 Dec 15;418 Pt 3(0 3):334-9. doi: 10.1016/j.mce.2015.01.043. Epub 2015 Feb 4. PMID: 25661537; PMCID: PMC4524798.\u003c/li\u003e\n\u003cli\u003eLuo Q, Wang CQ, Yang LY, Gao XM, Sun HT, Zhang Y, Zhang KL, Zhu Y, Zheng Y, Sheng YY, Lu L, Jia HL, Yu WQ, Liu J, Dong QZ, Qin LX. FOXQ1/NDRG1 axis exacerbates hepatocellular carcinoma initiation via enhancing crosstalk between fibroblasts and tumor cells. Cancer Lett. 2018 Mar 28;417:21-34. doi: 10.1016/j.canlet.2017.12.021. Epub 2017 Dec 15. PMID: 29248714.\u003c/li\u003e\n\u003cli\u003eXia L, Huang W, Tian D, Zhu H, Qi X, Chen Z, Zhang Y, Hu H, Fan D, Nie Y, Wu K. Overexpression of forkhead box C1 promotes tumor metastasis and indicates poor prognosis in hepatocellular carcinoma. Hepatology. 2013 Feb;57(2):610-24. doi: 10.1002/hep.26029. PMID: 22911555.\u003c/li\u003e\n\u003cli\u003eKalinichenko VV, Major ML, Wang X, Petrovic V, Kuechle J, Yoder HM, Dennewitz MB, Shin B, Datta A, Raychaudhuri P, Costa RH. Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Genes Dev. 2004 Apr 1;18(7):830-50. doi: 10.1101/gad.1200704. PMID: 15082532; PMCID: PMC387422.\u003c/li\u003e\n\u003cli\u003eDa BL, Suchman KI, Lau L, Rabiee A, He AR, Shetty K, Yu H, Wong LL, Amdur RL, Crawford JM, Fox SS, Grimaldi GM, Shah PK, Weinstein J, Bernstein D, Satapathy SK, Chambwe N, Xiang X, Mishra L. Pathogenesis to management of hepatocellular carcinoma. Genes Cancer. 2022 Dec 13;13:72-87. doi: 10.18632/genesandcancer.226. PMID: 36533190; PMCID: PMC9746873.\u003c/li\u003e\n\u003cli\u003eWang J, Zhu CP, Hu PF, Qian H, Ning BF, Zhang Q, Chen F, Liu J, Shi B, Zhang X, Xie WF. FOXA2 suppresses the metastasis of hepatocellular carcinoma partially through matrix metalloproteinase-9 inhibition. Carcinogenesis. 2014 Nov;35(11):2576-83. doi: 10.1093/carcin/bgu180. Epub 2014 Aug 20. PMID: 25142974.\u003c/li\u003e\n\u003cli\u003eQuintana-Bustamante O, Lan-Lan Smith S, Griessinger E, Reyal Y, Vargaftig J, Lister TA, Fitzgibbon J, Bonnet D. Overexpression of wild-type or mutants forms of CEBPA alter normal human hematopoiesis. Leukemia. 2012 Jul;26(7):1537-46. doi: 10.1038/leu.2012.38. Epub 2012 Feb 10. PMID: 22371011; PMCID: PMC3378638.\u003c/li\u003e\n\u003cli\u003eLeecharendkeat A, Tocharoentanaphol C, Auewarakul CU. CCAAT/enhancer binding protein-alpha polymorphisms occur more frequently than mutations in acute myeloid leukemia and exist across all cytogenetic risk groups and leukemia subtypes. Int J Cancer. 2008 Nov 15;123(10):2321-6. doi: 10.1002/ijc.23796. PMID: 18729193.\u003c/li\u003e\n\u003cli\u003eR\u0026aacute;zga F, Dvor\u0026aacute;kov\u0026aacute; D, Jurcek T, Jez\u0026iacute;skov\u0026aacute; I, Kr\u0026iacute;stkov\u0026aacute; Z, Mayer J. CEBPA gene mutational status: a complete screening using high-resolution melt curve analysis. Mol Diagn Ther. 2009;13(3):195-200. doi: 10.2165/01250444-200913030-00004. PMID: 19650672.\u003c/li\u003e\n\u003cli\u003eWilhelmson AS, Porse BT. CCAAT enhancer binding protein alpha (CEBPA) biallelic acute myeloid leukaemia: cooperating lesions, molecular mechanisms and clinical relevance. Br J Haematol. 2020 Aug;190(4):495-507. doi: 10.1111/bjh.16534. Epub 2020 Feb 21. PMID: 32086816; PMCID: PMC7496298.\u003c/li\u003e\n\u003cli\u003eHollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters ST, Zimmermann M, Peeters JK, Valk PJ, Balgobind BV, Sonneveld E, Kaspers GJ, de Bont ES, Trka J, Baruchel A, Creutzig U, Pieters R, Reinhardt D, Zwaan CM. Characterization of CEBPA mutations and promoter hypermethylation in pediatric acute myeloid leukemia. Haematologica. 2011 Mar;96(3):384-92. doi: 10.3324/haematol.2010.031336. Epub 2010 Dec 6. PMID: 21134981; PMCID: PMC3046269.\u003c/li\u003e\n\u003cli\u003eKantzer CG, Yang W, Grommisch D, Vikhe Patil K, Mak KH, Shirokova V, Genander M. ID1 and CEBPA coordinate epidermal progenitor cell differentiation. Development. 2022 Nov 15;149(22):dev201262. doi: 10.1242/dev.201262. Epub 2022 Nov 16. PMID: 36330928; PMCID: PMC9845743.\u003c/li\u003e\n\u003cli\u003eChen X, Zhou W, Song RH, Liu S, Wang S, Chen Y, Gao C, He C, Xiao J, Zhang L, Wang T, Liu P, Duan K, Cheng Z, Zhang C, Zhang J, Sun Y, Jackson F, Lan F, Liu Y, Xu Y, Wong JJ, Wang P, Yang H, Xiong Y, Chen T, Li Y, Ye D. Tumor suppressor CEBPA interacts with and inhibits DNMT3A activity. Sci Adv. 2022 Jan 28;8(4):eabl5220. doi: 10.1126/sciadv.abl5220. Epub 2022 Jan 26. PMID: 35080973; PMCID: PMC8791617.\u003c/li\u003e\n\u003cli\u003eEllsworth PN, Herring JA, Leifer AH, Ray JD, Elison WS, Poulson PD, Crabtree JE, Van Ry PM, Tessem JS. CEBPA Overexpression Enhances \u0026beta;-Cell Proliferation and Survival. Biology (Basel). 2024 Feb 9;13(2):110. doi: 10.3390/biology13020110. PMID: 38392328; PMCID: PMC10887016.\u003c/li\u003e\n\u003cli\u003eSetten RL, Lightfoot HL, Habib NA, Rossi JJ. Development of MTL-CEBPA: Small Activating RNA Drug for Hepatocellular Carcinoma. Curr Pharm Biotechnol. 2018;19(8):611-621. doi: 10.2174/1389201019666180611093428. PMID: 29886828; PMCID: PMC6204661.\u003c/li\u003e\n\u003cli\u003eHuang KW, Tan CP, Reebye V, Chee CE, Zacharoulis D, Habib R, Blakey DC, Rossi JJ, Habib N, Sodergren MH. MTL-CEBPA Combined with Immunotherapy or RFA Enhances Immunological Anti-Tumor Response in Preclinical Models. Int J Mol Sci. 2021 Aug 25;22(17):9168. doi: 10.3390/ijms22179168. PMID: 34502076; PMCID: PMC8431011.\u003c/li\u003e\n\u003cli\u003eWang C, Ren R, Hu H, Tan C, Han M, Wang X, Zheng Y. MiR-182 is up-regulated and targeting Cebpa in hepatocellular carcinoma. Chin J Cancer Res. 2014 Feb;26(1):17-29. doi: 10.3978/j.issn.1000-9604.2014.01.01. PMID: 24653623; PMCID: PMC3937760.\u003c/li\u003e\n\u003cli\u003eReebye V, Huang KW, Lin V, Jarvis S, Cutilas P, Dorman S, Ciriello S, Andrikakou P, Voutila J, Saetrom P, Mintz PJ, Reccia I, Rossi JJ, Huber H, Habib R, Kostomitsopoulos N, Blakey DC, Habib NA. Gene activation of CEBPA using saRNA: preclinical studies of the first in human saRNA drug candidate for liver cancer. Oncogene. 2018 Jun;37(24):3216-3228. doi: 10.1038/s41388-018-0126-2. Epub 2018 Mar 7. PMID: 29511346; PMCID: PMC6013054.\u003c/li\u003e\n\u003cli\u003eLu GD, Leung CH, Yan B, Tan CM, Low SY, Aung MO, Salto-Tellez M, Lim SG, Hooi SC. C/EBPalpha is up-regulated in a subset of hepatocellular carcinomas and plays a role in cell growth and proliferation. Gastroenterology. 2010 Aug;139(2):632-43, 643.e1-4. doi: 10.1053/j.gastro.2010.03.051. Epub 2010 Mar 27. PMID: 20347819.\u003c/li\u003e\n\u003cli\u003eHarigae H. GATA transcription factors and hematological diseases. Tohoku J Exp Med. 2006 Sep;210(1):1-9. doi: 10.1620/tjem.210.1. PMID: 16960339.\u003c/li\u003e\n\u003cli\u003eKatsumura KR, Bresnick EH; GATA Factor Mechanisms Group. The GATA factor revolution in hematology. Blood. 2017 Apr 13;129(15):2092-2102. doi: 10.1182/blood-2016-09-687871. Epub 2017 Feb 8. PMID: 28179282; PMCID: PMC5391619.\u003c/li\u003e\n\u003cli\u003eLentjes MH, Niessen HE, Akiyama Y, de Bru\u0026iuml;ne AP, Melotte V, van Engeland M. The emerging role of GATA transcription factors in development and disease. Expert Rev Mol Med. 2016 Mar 8;18:e3. doi: 10.1017/erm.2016.2. PMID: 26953528; PMCID: PMC4836206.\u003c/li\u003e\n\u003cli\u003eFujiwara T. GATA Transcription Factors: Basic Principles and Related Human Disorders. Tohoku J Exp Med. 2017 Jun;242(2):83-91. doi: 10.1620/tjem.242.83. PMID: 28566565.\u003c/li\u003e\n\u003cli\u003eBarrett DM, Gustafson KS, Wang J, Wang SZ, Ginder GD. A GATA factor mediates cell type-restricted induction of HLA-E gene transcription by gamma interferon. Mol Cell Biol. 2004 Jul;24(14):6194-204. doi: 10.1128/MCB.24.14.6194-6204.2004. PMID: 15226423; PMCID: PMC434230.\u003c/li\u003e\n\u003cli\u003eKeller T, Thompson CR. Cell type specificity of a diffusible inducer is determined by a GATA family transcription factor. Development. 2008 May;135(9):1635-45. doi: 10.1242/dev.020883. Epub 2008 Mar 26. PMID: 18367552; PMCID: PMC3942654.\u003c/li\u003e\n\u003cli\u003eZheng R, Blobel GA. GATA Transcription Factors and Cancer. Genes Cancer. 2010 Dec;1(12):1178-88. doi: 10.1177/1947601911404223. PMID: 21779441; PMCID: PMC3092280.\u003c/li\u003e\n\u003cli\u003eKhazaeli Najafabadi M, Mirzaeian E, Memar Montazerin S, Tavangar AR, Tabary M, Tavangar SM. Role of GATA3 in tumor diagnosis: A review. Pathol Res Pract. 2021 Oct;226:153611. doi: 10.1016/j.prp.2021.153611. Epub 2021 Sep 13. PMID: 34547599.\u003c/li\u003e\n\u003cli\u003eParviainen H, Kiiveri S, Bielinska M, Rahman N, Huhtaniemi IT, Wilson DB, Heikinheimo M. GATA transcription factors in adrenal development and tumors. Mol Cell Endocrinol. 2007 Feb;265-266:17-22. doi: 10.1016/j.mce.2006.12.033. Epub 2007 Jan 5. PMID: 17207921.\u003c/li\u003e\n\u003cli\u003eChou J, Provot S, Werb Z. GATA3 in development and cancer differentiation: cells GATA have it! J Cell Physiol. 2010 Jan;222(1):42-9. doi: 10.1002/jcp.21943. PMID: 19798694; PMCID: PMC2915440.\u003c/li\u003e\n\u003cli\u003eGonzalez RS, Wang J, Kraus T, Sullivan H, Adams AL, Cohen C. GATA-3 expression in male and female breast cancers: comparison of clinicopathologic parameters and prognostic relevance. Hum Pathol. 2013 Jun;44(6):1065-70. doi: 10.1016/j.humpath.2012.09.010. Epub 2012 Dec 23. PMID: 23266442.\u003c/li\u003e\n\u003cli\u003eOda H, Hedayati E, Lindstr\u0026ouml;m A, Shabo I. GATA-3 expression in breast cancer is related to intratumoral M2 macrophage infiltration and tumor differentiation. PLoS One. 2023 Mar 30;18(3):e0283003. doi: 10.1371/journal.pone.0283003. PMID: 36996051; PMCID: PMC10062580.\u003c/li\u003e\n\u003cli\u003eEnane FO, Shuen WH, Gu X, Quteba E, Przychodzen B, Makishima H, Bodo J, Ng J, Chee CL, Ba R, Seng Koh L, Lim J, Cheong R, Teo M, Hu Z, Ng KP, Maciejewski J, Radivoyevitch T, Chung A, Ooi LL, Tan YM, Cheow PC, Chow P, Chan CY, Lim KH, Yerian L, Hsi E, Toh HC, Saunthararajah Y. GATA4 loss of function in liver cancer impedes precursor to hepatocyte transition. J Clin Invest. 2017 Sep 1;127(9):3527-3542. doi: 10.1172/JCI93488. Epub 2017 Jul 31. PMID: 28758902; PMCID: PMC5669578.\u003c/li\u003e\n\u003cli\u003eSoini T, Haveri H, Elo JM, Kauppinen M, Kyr\u0026ouml;nlahti A, Salo MK, Lohi J, Andersson LC, Wilson DB, Heikinheimo M. Transcription factor GATA-4 is abundantly expressed in childhood but not in adult liver tumors. J Pediatr Gastroenterol Nutr. 2012 Jan;54(1):101-8. doi: 10.1097/MPG.0b013e31822d52cf. PMID: 21788913.\u003c/li\u003e\n\u003cli\u003eChen P, Liu X, Liu Y, Bao X, Wu Q. ARHGAP18 is Upregulated by Transcription Factor GATA1 Promotes the Proliferation and Invasion in Hepatocellular Carcinoma. Appl Biochem Biotechnol. 2024 Feb;196(2):679-689. doi: 10.1007/s12010-023-04459-0. Epub 2023 May 12. PMID: 37171759.\u003c/li\u003e\n\u003cli\u003eTan HW, Leung CO, Chan KK, Ho DW, Leung MS, Wong CM, Ng IO, Lo RC. Deregulated GATA6 modulates stem cell-like properties and metabolic phenotype in hepatocellular carcinoma. Int J Cancer. 2019 Oct 1;145(7):1860-1873. doi: 10.1002/ijc.32248. Epub 2019 Mar 28. PMID: 30834518.\u003c/li\u003e\n\u003cli\u003eSun W, Zhang Y, Wong KC, Liu K, Yang Y, Wu B, Tong JHM, Chan AWH, Chan HLY, Yu J. Increased expression of GATA zinc finger domain containing 1 through gene amplification promotes liver cancer by directly inducing phosphatase of regenerating liver 3. Hepatology. 2018 Jun;67(6):2302-2319. doi: 10.1002/hep.29750. Epub 2018 Mar 23. PMID: 29266303; PMCID: PMC6001784.\u003c/li\u003e\n\u003cli\u003eLv X, Xiang X, Wu Y, Liu Y, Xu R, Xiang Q, Lai G. GATA binding protein 4 promotes the expression and transcription of hepatitis B virus by facilitating hepatocyte nuclear factor 4 alpha in vitro. Virol J. 2021 Sep 28;18(1):196. doi: 10.1186/s12985-021-01668-z. PMID: 34583732; PMCID: PMC8479913.\u003c/li\u003e\n\u003cli\u003eKivel\u0026auml; R, Salmela I, Nguyen YH, Petrova TV, Koistinen HA, Wiener Z, Alitalo K. The transcription factor Prox1 is essential for satellite cell differentiation and muscle fibre-type regulation. Nat Commun. 2016 Oct 12;7:13124. doi: 10.1038/ncomms13124. PMID: 27731315; PMCID: PMC5064023.\u003c/li\u003e\n\u003cli\u003eGizaw NY, Kallio P, Punger T, Gucciardo E, Haglund C, B\u0026ouml;hling T, Lehti K, Sampo M, Alitalo K, Kivel\u0026auml; R. PROX1 transcription factor controls rhabdomyosarcoma growth, stemness, myogenic properties and therapeutic targets. Proc Natl Acad Sci U S A. 2022 Dec 6;119(49):e2116220119. doi: 10.1073/pnas.2116220119. Epub 2022 Dec 2. PMID: 36459642; PMCID: PMC9894179.\u003c/li\u003e\n\u003cli\u003eHong YK, Harvey N, Noh YH, Schacht V, Hirakawa S, Detmar M, Oliver G. Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn. 2002 Nov;225(3):351-7. doi: 10.1002/dvdy.10163. PMID: 12412020.\u003c/li\u003e\n\u003cli\u003eDyer MA, Livesey FJ, Cepko CL, Oliver G. Prox1 function controls progenitor cell proliferation and horizontal cell genesis in the mammalian retina. Nat Genet. 2003 May;34(1):53-8. doi: 10.1038/ng1144. PMID: 12692551.\u003c/li\u003e\n\u003cli\u003eLee S, Kang J, Yoo J, Ganesan SK, Cook SC, Aguilar B, Ramu S, Lee J, Hong YK. Prox1 physically and functionally interacts with COUP-TFII to specify lymphatic endothelial cell fate. Blood. 2009 Feb 19;113(8):1856-9. doi: 10.1182/blood-2008-03-145789. Epub 2008 Sep 24. PMID: 18815287; PMCID: PMC2647678.\u003c/li\u003e\n\u003cli\u003eElsir T, Smits A, Lindstr\u0026ouml;m MS, Nist\u0026eacute;r M. Transcription factor PROX1: its role in development and cancer. Cancer Metastasis Rev. 2012 Dec;31(3-4):793-805. doi: 10.1007/s10555-012-9390-8. PMID: 22733308.\u003c/li\u003e\n\u003cli\u003eZhu L, Tian Q, Gao H, Wu K, Wang B, Ge G, Jiang S, Wang K, Zhou C, He J, Liu P, Ren Y, Wang B. PROX1 promotes breast cancer invasion and metastasis through WNT/\u0026beta;-catenin pathway via interacting with hnRNPK. Int J Biol Sci. 2022 Feb 28;18(5):2032-2046. doi: 10.7150/ijbs.68960. PMID: 35342346; PMCID: PMC8935233.\u003c/li\u003e\n\u003cli\u003eMiettinen M, Wang ZF. Prox1 transcription factor as a marker for vascular tumors-evaluation of 314 vascular endothelial and 1086 nonvascular tumors. Am J Surg Pathol. 2012 Mar;36(3):351-9. doi: 10.1097/PAS.0b013e318236c312. PMID: 22067331; PMCID: PMC3288441.\u003c/li\u003e\n\u003cli\u003eRudzińska M, Mikula M, Arczewska KD, Gajda E, Sabalińska S, Stępień T, Ostrowski J, Czarnocka B. Transcription Factor Prospero Homeobox 1 (PROX1) as a Potential Angiogenic Regulator of Follicular Thyroid Cancer Dissemination. Int J Mol Sci. 2019 Nov 10;20(22):5619. doi: 10.3390/ijms20225619. PMID: 31717665; PMCID: PMC6888435.\u003c/li\u003e\n\u003cli\u003ePark YL, Myung E, Park SY, Kim N, Oak CY, Myung DS, Cho SB, Lee WS, Kweon SS, Kim HS, Joo YE. Impact of prospero homeobox-1 on tumor cell behavior and prognosis in colorectal cancer. Am J Cancer Res. 2015 Oct 15;5(11):3286-300. PMID: 26807311; PMCID: PMC4697677.\u003c/li\u003e\n\u003cli\u003eMichail A, Gkikas D, Stellas D, Kaltezioti V, Politis PK. Prox1 Suppresses the Proliferation of Breast Cancer Cells via Direct Inhibition of c-Myc Gene Expression. Cells. 2023 Jul 17;12(14):1869. doi: 10.3390/cells12141869. PMID: 37508533; PMCID: PMC10377922.\u003c/li\u003e\n\u003cli\u003eNtikoudi E, Pergaris A, Kykalos S, Politi E, Theocharis S. The Role of PROX1 in Neoplasia: A Key Player Often Overlooked. Diagnostics (Basel). 2022 Jul 4;12(7):1624. doi: 10.3390/diagnostics12071624. PMID: 35885529; PMCID: PMC9320018.\u003c/li\u003e\n\u003cli\u003eJernman J, Kallio P, Hagstr\u0026ouml;m J, V\u0026auml;lim\u0026auml;ki MJ, Haapasalo H, Alitalo K, Arola J, Haglund C. PROX1 is involved in progression of rectal neuroendocrine tumors, NETs. Virchows Arch. 2015 Sep;467(3):279-84. doi: 10.1007/s00428-015-1795-7. Epub 2015 Jun 11. PMID: 26063416.\u003c/li\u003e\n\u003cli\u003eLiu Y, Zhang JB, Qin Y, Wang W, Wei L, Teng Y, Guo L, Zhang B, Lin Z, Liu J, Ren ZG, Ye QH, Xie Y. PROX1 promotes hepatocellular carcinoma metastasis by way of up-regulating hypoxia-inducible factor 1\u0026alpha; expression and protein stability. Hepatology. 2013 Aug;58(2):692-705. doi: 10.1002/hep.26398. PMID: 23505027.\u003c/li\u003e\n\u003cli\u003eShimoda M, Takahashi M, Yoshimoto T, Kono T, Ikai I, Kubo H. A homeobox protein, prox1, is involved in the differentiation, proliferation, and prognosis in hepatocellular carcinoma. Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6005-11. doi: 10.1158/1078-0432.CCR-06-0712. PMID: 17062673.\u003c/li\u003e\n\u003cli\u003eLiu Y, Ye X, Zhang JB, Ouyang H, Shen Z, Wu Y, Wang W, Wu J, Tao S, Yang X, Qiao K, Zhang J, Liu J, Fu Q, Xie Y. PROX1 promotes hepatocellular carcinoma proliferation and sorafenib resistance by enhancing \u0026beta;-catenin expression and nuclear translocation. Oncogene. 2015 Oct 29;34(44):5524-35. doi: 10.1038/onc.2015.7. Epub 2015 Feb 16. PMID: 25684142.\u003c/li\u003e\n\u003cli\u003eKwon S, Ban K, Hong YK, Sung JS, Choi I. PROX1, a Key Mediator of the Anti-Proliferative Effect of Rapamycin on Hepatocellular Carcinoma Cells. Cells. 2022 Jan 27;11(3):446. doi: 10.3390/cells11030446. PMID: 35159256; PMCID: PMC8834064.\u003c/li\u003e\n\u003cli\u003eChang TM, Hung WC. The homeobox transcription factor Prox1 inhibits proliferation of hepatocellular carcinoma cells by inducing p53-dependent senescence-like phenotype. Cancer Biol Ther. 2013 Mar;14(3):222-9. doi: 10.4161/cbt.23293. Epub 2013 Jan 4. PMID: 23291986; PMCID: PMC3595304.\u003c/li\u003e\n\u003cli\u003eKim YJ, Yoo JE, Jeon Y, Chong JU, Choi GH, Song DG, Jung SH, Oh BK, Park YN. Suppression of PROX1-mediated TERT expression in hepatitis B viral hepatocellular carcinoma. Int J Cancer. 2018 Dec 15;143(12):3155-3168. doi: 10.1002/ijc.31731. Epub 2018 Sep 27. PMID: 29987895.\u003c/li\u003e\n\u003cli\u003eDudas J, Mansuroglu T, Moriconi F, Haller F, Wilting J, Lorf T, F\u0026uuml;zesi L, Ramadori G. Altered regulation of Prox1-gene-expression in liver tumors. BMC Cancer. 2008 Apr 9;8:92. doi: 10.1186/1471-2407-8-92. PMID: 18400094; PMCID: PMC2359759.\u003c/li\u003e\n\u003cli\u003eJo A, Denduluri S, Zhang B, Wang Z, Yin L, Yan Z, Kang R, Shi LL, Mok J, Lee MJ, Haydon RC. The versatile functions of Sox9 in development, stem cells, and human diseases. Genes Dis. 2014 Dec;1(2):149-161. doi: 10.1016/j.gendis.2014.09.004. PMID: 25685828; PMCID: PMC4326072.\u003c/li\u003e\n\u003cli\u003eSymon A, Harley V. SOX9: A genomic view of tissue specific expression and action. Int J Biochem Cell Biol. 2017 Jun;87:18-22. doi: 10.1016/j.biocel.2017.03.005. Epub 2017 Mar 16. PMID: 28323209.\u003c/li\u003e\n\u003cli\u003eRichtig G, Aigelsreiter A, Schwarzenbacher D, Ress AL, Adiprasito JB, Stiegelbauer V, Hoefler G, Schauer S, Kiesslich T, Kornprat P, Winder T, Eisner F, Gerger A, Stoeger H, Stauber R, Lackner C, Pichler M. SOX9 is a proliferation and stem cell factor in hepatocellular carcinoma and possess widespread prognostic significance in different cancer types. PLoS One. 2017 Nov 9;12(11):e0187814. doi: 10.1371/journal.pone.0187814. PMID: 29121666; PMCID: PMC5679634.\u003c/li\u003e\n\u003cli\u003eAguilar-Medina M, Avenda\u0026ntilde;o-F\u0026eacute;lix M, Liz\u0026aacute;rraga-Verdugo E, Berm\u0026uacute;dez M, Romero-Quintana JG, Ramos-Payan R, Ru\u0026iacute;z-Garc\u0026iacute;a E, L\u0026oacute;pez-Camarillo C. SOX9 Stem-Cell Factor: Clinical and Functional Relevance in Cancer. J Oncol. 2019 Apr 1;2019:6754040. doi: 10.1155/2019/6754040. PMID: 31057614; PMCID: PMC6463569.\u003c/li\u003e\n\u003cli\u003eGracz AD, Ramalingam S, Magness ST. Sox9 expression marks a subset of CD24-expressing small intestine epithelial stem cells that form organoids in vitro. Am J Physiol Gastrointest Liver Physiol. 2010 May;298(5):G590-600. doi: 10.1152/ajpgi.00470.2009. Epub 2010 Feb 25. PMID: 20185687; PMCID: PMC2867430.\u003c/li\u003e\n\u003cli\u003eScott CE, Wynn SL, Sesay A, Cruz C, Cheung M, Gomez Gaviro MV, Booth S, Gao B, Cheah KS, Lovell-Badge R, Briscoe J. SOX9 induces and maintains neural stem cells. Nat Neurosci. 2010 Oct;13(10):1181-9. doi: 10.1038/nn.2646. PMID: 20871603.\u003c/li\u003e\n\u003cli\u003eFabra-Beser J, Alves Medeiros de Araujo J, Marques-Coelho D, Goff LA, Costa MR, M\u0026uuml;ller U, Gil-Sanz C. Differential Expression Levels of Sox9 in Early Neocortical Radial Glial Cells Regulate the Decision between Stem Cell Maintenance and Differentiation. J Neurosci. 2021 Aug 18;41(33):6969-6986. doi: 10.1523/JNEUROSCI.2905-20.2021. Epub 2021 Jul 15. PMID: 34266896; PMCID: PMC8372026.\u003c/li\u003e\n\u003cli\u003ePanda M, Tripathi SK, Biswal BK. SOX9: An emerging driving factor from cancer progression to drug resistance. Biochim Biophys Acta Rev Cancer. 2021 Apr;1875(2):188517. doi: 10.1016/j.bbcan.2021.188517. Epub 2021 Jan 29. PMID: 33524528.\u003c/li\u003e\n\u003cli\u003eAldaz P, Otaegi-Ugartemendia M, Saenz-Anto\u0026ntilde;anzas A, Garcia-Puga M, Moreno-Valladares M, Flores JM, Gerovska D, Arauzo-Bravo MJ, Sampr\u0026oacute;n N, Matheu A, Carrasco-Garcia E. SOX9 promotes tumor progression through the axis BMI1-p21\u003csup\u003eCIP\u003c/sup\u003e. Sci Rep. 2020 Jan 15;10(1):357. doi: 10.1038/s41598-019-57047-w. PMID: 31941916; PMCID: PMC6962164.\u003c/li\u003e\n\u003cli\u003eWehrli BM, Huang W, De Crombrugghe B, Ayala AG, Czerniak B. Sox9, a master regulator of chondrogenesis, distinguishes mesenchymal chondrosarcoma from other small blue round cell tumors. Hum Pathol. 2003 Mar;34(3):263-9. doi: 10.1053/hupa.2003.41. PMID: 12673561.\u003c/li\u003e\n\u003cli\u003eSardar D, Chen HC, Reyes A, Varadharajan S, Jain A, Mohila C, Curry R, Lozzi B, Rajendran K, Cervantes A, Yu K, Jalali A, Rao G, Mack SC, Deneen B. Sox9 directs divergent epigenomic states in brain tumor subtypes. Proc Natl Acad Sci U S A. 2022 Jul 19;119(29):e2202015119. doi: 10.1073/pnas.2202015119. Epub 2022 Jul 15. PMID: 35858326; PMCID: PMC9303974.\u003c/li\u003e\n\u003cli\u003eZhong H, Lu W, Tang Y, Wiel C, Wei Y, Cao J, Riedlinger G, Papagiannakopoulos T, Guo JY, Bergo MO, Kang Y, Ganesan S, Sabaawy HE, Pine SR. SOX9 drives KRAS-induced lung adenocarcinoma progression and suppresses anti-tumor immunity. Oncogene. 2023 Jun;42(27):2183-2194. doi: 10.1038/s41388-023-02715-5. Epub 2023 May 31. PMID: 37258742.\u003c/li\u003e\n\u003cli\u003eYuan X, Huang L, Luo W, Zhao Y, Nashan B, Yu F, Liu Y. Diagnostic and Prognostic Significances of SOX9 in Thymic Epithelial Tumor. Front Oncol. 2021 Oct 28;11:708735. doi: 10.3389/fonc.2021.708735. PMID: 34778027; PMCID: PMC8580949.\u003c/li\u003e\n\u003cli\u003eMa Y, Shepherd J, Zhao D, Bollu LR, Tahaney WM, Hill J, Zhang Y, Mazumdar A, Brown PH. SOX9 Is Essential for Triple-Negative Breast Cancer Cell Survival and Metastasis. Mol Cancer Res. 2020 Dec;18(12):1825-1838. doi: 10.1158/1541-7786.MCR-19-0311. Epub 2020 Jul 13. PMID: 32661114; PMCID: PMC7718423.\u003c/li\u003e\n\u003cli\u003eRuzinova MB, Ma C, Brunt EM, Goss CW, Vachharajani N, Chapman WC, Liu TC. SOX9 Expression Is Superior to Other Stem Cell Markers K19 and EpCAM in Predicting Prognosis in Hepatocellular Carcinoma. Am J Surg Pathol. 2023 Jan 1;47(1):1-11. doi: 10.1097/PAS.0000000000001990. Epub 2022 Nov 3. PMID: 36322988.\u003c/li\u003e\n\u003cli\u003eGuo C, Zhou S, Yi W, Yang P, Li O, Liu J, Peng C. SOX9/MKLN1-AS Axis Induces Hepatocellular Carcinoma Proliferation and Epithelial-Mesenchymal Transition. Biochem Genet. 2022 Dec;60(6):1914-1933. doi: 10.1007/s10528-022-10196-6. Epub 2022 Feb 9. PMID: 35138470.\u003c/li\u003e\n\u003cli\u003eRen Z, Chen Y, Shi L, Shao F, Sun Y, Ge J, Zhang J, Zang Y. Sox9/CXCL5 axis facilitates tumour cell growth and invasion in hepatocellular carcinoma. FEBS J. 2022 Jun;289(12):3535-3549. doi: 10.1111/febs.16357. Epub 2022 Jan 25. PMID: 35038357.\u003c/li\u003e\n\u003cli\u003eLiu C, Liu L, Chen X, Cheng J, Zhang H, Shen J, Shan J, Xu Y, Yang Z, Lai M, Qian C. Sox9 regulates self-renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma. Hepatology. 2016 Jul;64(1):117-29. doi: 10.1002/hep.28509. Epub 2016 Mar 25. PMID: 26910875.\u003c/li\u003e\n\u003cli\u003eKawai T, Yasuchika K, Ishii T, Miyauchi Y, Kojima H, Yamaoka R, Katayama H, Yoshitoshi EY, Ogiso S, Kita S, Yasuda K, Fukumitsu K, Komori J, Hatano E, Kawaguchi Y, Uemoto S. SOX9 is a novel cancer stem cell marker surrogated by osteopontin in human hepatocellular carcinoma. Sci Rep. 2016 Jul 26;6:30489. doi: 10.1038/srep30489. PMID: 27457505; PMCID: PMC4960550.\u003c/li\u003e\n\u003cli\u003eLiu Y, Zhuo S, Zhou Y, Ma L, Sun Z, Wu X, Wang XW, Gao B, Yang Y. Yap-Sox9 signaling determines hepatocyte plasticity and lineage-specific hepatocarcinogenesis. J Hepatol. 2022 Mar;76(3):652-664. doi: 10.1016/j.jhep.2021.11.010. Epub 2021 Nov 15. PMID: 34793870; PMCID: PMC8858854.\u003c/li\u003e\n\u003cli\u003eLi B, Liu D, Yang P, Li HY, Wang D. miR-613 inhibits liver cancer stem cell expansion by regulating SOX9 pathway. Gene. 2019 Jul 30;707:78-85. doi: 10.1016/j.gene.2019.05.015. Epub 2019 May 7. PMID: 31075412.\u003c/li\u003e\n\u003cli\u003ePierfelice TJ, Schreck KC, Eberhart CG, Gaiano N. Notch, neural stem cells, and brain tumors. Cold Spring Harb Symp Quant Biol. 2008;73:367-75. doi: 10.1101/sqb.2008.73.013. Epub 2008 Nov 6. PMID: 19022772; PMCID: PMC4510468.\u003c/li\u003e\n\u003cli\u003eDontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res. 2004;6(6):R605-15. doi: 10.1186/bcr920. Epub 2004 Aug 16. PMID: 15535842; PMCID: PMC1064073.\u003c/li\u003e\n\u003cli\u003eHori K, Sen A, Artavanis-Tsakonas S. Notch signaling at a glance. J Cell Sci. 2013 May 15;126(Pt 10):2135-40. doi: 10.1242/jcs.127308. Epub 2013 May 31. PMID: 23729744; PMCID: PMC3672934.\u003c/li\u003e\n\u003cli\u003eGaiano N, Fishell G. The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci. 2002;25:471-90. doi: 10.1146/annurev.neuro.25.030702.130823. Epub 2002 Mar 25. PMID: 12052917.\u003c/li\u003e\n\u003cli\u003eFi\u0026uacute;za UM, Arias AM. Cell and molecular biology of Notch. J Endocrinol. 2007 Sep;194(3):459-74. doi: 10.1677/JOE-07-0242. PMID: 17761886.\u003c/li\u003e\n\u003cli\u003eD\u0026apos;Assoro AB, Leon-Ferre R, Braune EB, Lendahl U. Roles of Notch Signaling in the Tumor Microenvironment. Int J Mol Sci. 2022 Jun 2;23(11):6241. doi: 10.3390/ijms23116241. PMID: 35682918; PMCID: PMC9181414.\u003c/li\u003e\n\u003cli\u003eBigas A, D\u0026apos;Altri T, Espinosa L. The Notch pathway in hematopoietic stem cells. Curr Top Microbiol Immunol. 2012;360:1-18. doi: 10.1007/82_2012_229. PMID: 22692832.\u003c/li\u003e\n\u003cli\u003eNowell CS, Radtke F. Notch as a tumour suppressor. Nat Rev Cancer. 2017 Mar;17(3):145-159. doi: 10.1038/nrc.2016.145. Epub 2017 Feb 3. PMID: 28154375.\u003c/li\u003e\n\u003cli\u003eMeurette O, Mehlen P. Notch Signaling in the Tumor Microenvironment. Cancer Cell. 2018 Oct 8;34(4):536-548. doi: 10.1016/j.ccell.2018.07.009. Epub 2018 Aug 23. PMID: 30146333.\u003c/li\u003e\n\u003cli\u003eCapaccione KM, Pine SR. The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis. 2013 Jul;34(7):1420-30. doi: 10.1093/carcin/bgt127. Epub 2013 Apr 12. PMID: 23585460; PMCID: PMC3697894.\u003c/li\u003e\n\u003cli\u003eFerreira A, Aster JC. Notch signaling in cancer: Complexity and challenges on the path to clinical translation. Semin Cancer Biol. 2022 Oct;85:95-106. doi: 10.1016/j.semcancer.2021.04.008. Epub 2021 Apr 20. PMID: 33862222.\u003c/li\u003e\n\u003cli\u003eLi X, Yan X, Wang Y, Kaur B, Han H, Yu J. The Notch signaling pathway: a potential target for cancer immunotherapy. J Hematol Oncol. 2023 May 2;16(1):45. doi: 10.1186/s13045-023-01439-z. PMID: 37131214; PMCID: PMC10155406.\u003c/li\u003e\n\u003cli\u003eAster JC, Pear WS, Blacklow SC. The Varied Roles of Notch in Cancer. Annu Rev Pathol. 2017 Jan 24;12:245-275. doi: 10.1146/annurev-pathol-052016-100127. Epub 2016 Dec 5. PMID: 27959635; PMCID: PMC5933931.\u003c/li\u003e\n\u003cli\u003eZhou B, Lin W, Long Y, Yang Y, Zhang H, Wu K, Chu Q. Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct Target Ther. 2022 Mar 24;7(1):95. doi: 10.1038/s41392-022-00934-y. PMID: 35332121; PMCID: PMC8948217.\u003c/li\u003e\n\u003cli\u003eHu YY, Zheng MH, Zhang R, Liang YM, Han H. Notch signaling pathway and cancer metastasis. Adv Exp Med Biol. 2012;727:186-98. doi: 10.1007/978-1-4614-0899-4_14. PMID: 22399348.\u003c/li\u003e\n\u003cli\u003eZhu C, Ho YJ, Salomao MA, Dapito DH, Bartolome A, Schwabe RF, Lee JS, Lowe SW, Pajvani UB. Notch activity characterizes a common hepatocellular carcinoma subtype with unique molecular and clinicopathologic features. J Hepatol. 2021 Mar;74(3):613-626. doi: 10.1016/j.jhep.2020.09.032. Epub 2020 Oct 8. PMID: 33038431; PMCID: PMC7897246.\u003c/li\u003e\n\u003cli\u003eVillanueva A, Alsinet C, Yanger K, Hoshida Y, Zong Y, Toffanin S, Rodriguez-Carunchio L, Sol\u0026eacute; M, Thung S, Stanger BZ, Llovet JM. Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice. Gastroenterology. 2012 Dec;143(6):1660-1669.e7. doi: 10.1053/j.gastro.2012.09.002. Epub 2012 Sep 11. PMID: 22974708; PMCID: PMC3505826.\u003c/li\u003e\n\u003cli\u003eViatour P, Ehmer U, Saddic LA, Dorrell C, Andersen JB, Lin C, Zmoos AF, Mazur PK, Schaffer BE, Ostermeier A, Vogel H, Sylvester KG, Thorgeirsson SS, Grompe M, Sage J. Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J Exp Med. 2011 Sep 26;208(10):1963-76. doi: 10.1084/jem.20110198. Epub 2011 Aug 29. PMID: 21875955; PMCID: PMC3182062.\u003c/li\u003e\n\u003cli\u003eSun L, Sun G, Yu Y, Coy DH. Is Notch Signaling a Specific Target in Hepatocellular Carcinoma? Anticancer Agents Med Chem. 2015;15(7):809-15. doi: 10.2174/1871520615666150202102809. PMID: 25642981.\u003c/li\u003e\n\u003cli\u003eClotman F, Lannoy VJ, Reber M, Cereghini S, Cassiman D, Jacquemin P, Roskams T, Rousseau GG, Lemaigre FP. The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development. 2002 Apr;129(8):1819-28. doi: 10.1242/dev.129.8.1819. PMID: 11934848.\u003c/li\u003e\n\u003cli\u003ePierreux CE, Vanhorenbeeck V, Jacquemin P, Lemaigre FP, Rousseau GG. The transcription factor hepatocyte nuclear factor-6/Onecut-1 controls the expression of its paralog Onecut-3 in developing mouse endoderm. J Biol Chem. 2004 Dec 3;279(49):51298-304. doi: 10.1074/jbc.M409038200. Epub 2004 Sep 20. PMID: 15381696.\u003c/li\u003e\n\u003cli\u003eZhang H, Ables ET, Pope CF, Washington MK, Hipkens S, Means AL, Path G, Seufert J, Costa RH, Leiter AB, Magnuson MA, Gannon M. Multiple, temporal-specific roles for HNF6 in pancreatic endocrine and ductal differentiation. Mech Dev. 2009 Dec;126(11-12):958-73. doi: 10.1016/j.mod.2009.09.006. Epub 2009 Sep 18. PMID: 19766716; PMCID: PMC2783291.\u003c/li\u003e\n\u003cli\u003eLandry C, Clotman F, Hioki T, Oda H, Picard JJ, Lemaigre FP, Rousseau GG. HNF-6 is expressed in endoderm derivatives and nervous system of the mouse embryo and participates to the cross-regulatory network of liver-enriched transcription factors. Dev Biol. 1997 Dec 15;192(2):247-57. doi: 10.1006/dbio.1997.8757. PMID: 9441665.\u003c/li\u003e\n\u003cli\u003eAudouard E, Schakman O, Ginion A, Bertrand L, Gailly P, Clotman F. The Onecut transcription factor HNF-6 contributes to proper reorganization of Purkinje cells during postnatal cerebellum development. Mol Cell Neurosci. 2013 Sep;56:159-68. doi: 10.1016/j.mcn.2013.05.001. Epub 2013 May 10. PMID: 23669529.\u003c/li\u003e\n\u003cli\u003eJiang K, Jiao Y, Liu Y, Fu D, Geng H, Chen L, Chen H, Shen X, Sun L, Ding K. HNF6 promotes tumor growth in colorectal cancer and enhances liver metastasis in mouse model. J Cell Physiol. 2019 Apr;234(4):3675-3684. doi: 10.1002/jcp.27140. Epub 2018 Sep 7. PMID: 30256389.\u003c/li\u003e\n\u003cli\u003eLehner F, Kulik U, Klempnauer J, Borlak J. The hepatocyte nuclear factor 6 (HNF6) and FOXA2 are key regulators in colorectal liver metastases. FASEB J. 2007 May;21(7):1445-62. doi: 10.1096/fj.06-6575com. Epub 2007 Feb 5. PMID: 17283222.\u003c/li\u003e\n\u003cli\u003eYuan XW, Wang DM, Hu Y, Tang YN, Shi WW, Guo XJ, Song JG. Hepatocyte nuclear factor 6 suppresses the migration and invasive growth of lung cancer cells through p53 and the inhibition of epithelial-mesenchymal transition. J Biol Chem. 2013 Oct 25;288(43):31206-16. doi: 10.1074/jbc.M113.480285. Epub 2013 Sep 10. PMID: 24022481; PMCID: PMC3829431.\u003c/li\u003e\n\u003cli\u003ePekala KR, Ma X, Kropp PA, Petersen CP, Hudgens CW, Chung CH, Shi C, Merchant NB, Maitra A, Means AL, Gannon MA. Loss of HNF6 expression correlates with human pancreatic cancer progression. Lab Invest. 2014 May;94(5):517-27. doi: 10.1038/labinvest.2014.47. Epub 2014 Mar 17. PMID: 24638272; PMCID: PMC4068339.\u003c/li\u003e\n\u003cli\u003eYuan XW, Wang DM, Hu Y, Tang YN, Shi WW, Guo XJ, Song JG. Hepatocyte nuclear factor 6 suppresses the migration and invasive growth of lung cancer cells through p53 and the inhibition of epithelial-mesenchymal transition. J Biol Chem. 2013 Oct 25;288(43):31206-16. doi: 10.1074/jbc.M113.480285. Epub 2013 Sep 10. PMID: 24022481; PMCID: PMC3829431.\u003c/li\u003e\n\u003cli\u003eSun H, Tang H, Xie D, Jia Z, Ma Z, Wei D, Mishra L, Gao Y, Zheng S, Xie K, Peng Z. Kr\u0026uuml;ppel-like Factor 4 Blocks Hepatocellular Carcinoma Dedifferentiation and Progression through Activation of Hepatocyte Nuclear Factor-6. Clin Cancer Res. 2016 Jan 15;22(2):502-12. doi: 10.1158/1078-0432.CCR-15-0528. Epub 2015 Sep 2. PMID: 26338995; PMCID: PMC4715982.\u003c/li\u003e\n\u003cli\u003eLehner F, Kulik U, Klempnauer J, Borlak J. Inhibition of the liver enriched protein FOXA2 recovers HNF6 activity in human colon carcinoma and liver hepatoma cells. PLoS One. 2010 Oct 13;5(10):e13344. doi: 10.1371/journal.pone.0013344. PMID: 20967225; PMCID: PMC2954183.\u003c/li\u003e\n\u003cli\u003eHayashi Y, Wang W, Ninomiya T, Nagano H, Ohta K, Itoh H. Liver enriched transcription factors and differentiation of hepatocellular carcinoma. Mol Pathol. 1999 Feb;52(1):19-24. doi: 10.1136/mp.52.1.19. PMID: 10439834; PMCID: PMC395665.\u003c/li\u003e\n\u003cli\u003eRausa F, Samadani U, Ye H, Lim L, Fletcher CF, Jenkins NA, Copeland NG, Costa RH. The cut-homeodomain transcriptional activator HNF-6 is coexpressed with its target gene HNF-3 beta in the developing murine liver and pancreas. Dev Biol. 1997 Dec 15;192(2):228-46. doi: 10.1006/dbio.1997.8744. PMID: 9441664.\u003c/li\u003e\n\u003cli\u003eKropp PA, Gannon M. Onecut transcription factors in development and disease. Trends Dev Biol. 2016;9:43-57. PMID: 28018056; PMCID: PMC5176019.\u003c/li\u003e\n\u003cli\u003eMargagliotti S, Clotman F, Pierreux CE, Beaudry JB, Jacquemin P, Rousseau GG, Lemaigre FP. The Onecut transcription factors HNF-6/OC-1 and OC-2 regulate early liver expansion by controlling hepatoblast migration. Dev Biol. 2007 Nov 15;311(2):579-89. doi: 10.1016/j.ydbio.2007.09.013. Epub 2007 Sep 16. PMID: 17936262.\u003c/li\u003e\n\u003cli\u003eFreeman MR, Rotinen M, You S. ONECUT2 as a new therapeutic target in androgen receptor-indifferent prostate cancer. Transl Cancer Res. 2019 Nov;8(7):2677-2679. doi: 10.21037/tcr.2019.10.15. PMID: 35117025; PMCID: PMC8798022.\u003c/li\u003e\n\u003cli\u003eKropp PA, Gannon M. Onecut transcription factors in development and disease. Trends Dev Biol. 2016;9:43-57. PMID: 28018056; PMCID: PMC5176019.\u003c/li\u003e\n\u003cli\u003eYu J, Li D, Jiang H. Emerging role of ONECUT2 in tumors. Oncol Lett. 2020 Dec;20(6):328. doi: 10.3892/ol.2020.12192. Epub 2020 Oct 6. PMID: 33101497; PMCID: PMC7577075.\u003c/li\u003e\n\u003cli\u003eKaochar S, Mitsiades N. Multimodal action of ONECUT2 in driving neuroendocrine prostate cancer. Transl Cancer Res. 2019 Mar;8(Suppl 2):S198-S203. doi: 10.21037/tcr.2019.02.08. PMID: 31360645; PMCID: PMC6662936.\u003c/li\u003e\n\u003cli\u003eRotinen M, You S, Yang J, Coetzee SG, Reis-Sobreiro M, Huang WC, Huang F, Pan X, Y\u0026aacute;\u0026ntilde;ez A, Hazelett DJ, Chu CY, Steadman K, Morrissey CM, Nelson PS, Corey E, Chung LWK, Freedland SJ, Di Vizio D, Garraway IP, Murali R, Knudsen BS, Freeman MR. ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis. Nat Med. 2018 Dec;24(12):1887-1898. doi: 10.1038/s41591-018-0241-1. Epub 2018 Nov 26. PMID: 30478421; PMCID: PMC6614557.\u003c/li\u003e\n\u003cli\u003eRotinen M, You S, Yang J, Coetzee SG, Reis-Sobreiro M, Huang WC, Huang F, Pan X, Y\u0026aacute;\u0026ntilde;ez A, Hazelett DJ, Chu CY, Steadman K, Morrissey CM, Nelson PS, Corey E, Chung LWK, Freedland SJ, Di Vizio D, Garraway IP, Murali R, Knudsen BS, Freeman MR. ONECUT2 is a targetable master regulator of lethal prostate cancer that suppresses the androgen axis. Nat Med. 2018 Dec;24(12):1887-1898. doi: 10.1038/s41591-018-0241-1. Epub 2018 Nov 26. PMID: 30478421; PMCID: PMC6614557.\u003c/li\u003e\n\u003cli\u003eLiu D, Zhang T, Chen X, Zhang B, Wang Y, Xie M, Ji X, Sun M, Huang W, Xia L. ONECUT2 facilitates hepatocellular carcinoma metastasis by transcriptionally upregulating FGF2 and ACLY. Cell Death Dis. 2021 Nov 27;12(12):1113. doi: 10.1038/s41419-021-04410-3. Erratum in: Cell Death Dis. 2021 Dec 23;13(1):28. PMID: 34839358; PMCID: PMC8627506.\u003c/li\u003e\n\u003cli\u003eYu J, Li D, Jiang H. Emerging role of ONECUT2 in tumors. Oncol Lett. 2020 Dec;20(6):328. doi: 10.3892/ol.2020.12192. Epub 2020 Oct 6. PMID: 33101497; PMCID: PMC7577075.\u003c/li\u003e\n\u003cli\u003eHolterman AX, Tan Y, Kim W, Yoo KW, Costa RH. Diminished hepatic expression of the HNF-6 transcription factor during bile duct obstruction. Hepatology. 2002 Jun;35(6):1392-9. doi: 10.1053/jhep.2002.33680. PMID: 12029624.\u003c/li\u003e\n\u003cli\u003eSamadani U, Costa RH. The transcriptional activator hepatocyte nuclear factor 6 regulates liver gene expression. Mol Cell Biol. 1996 Nov;16(11):6273-84. doi: 10.1128/MCB.16.11.6273. PMID: 8887657; PMCID: PMC231630.\u003c/li\u003e\n\u003cli\u003eLau HH, Ng NHJ, Loo LSW, Jasmen JB, Teo AKK. The molecular functions of hepatocyte nuclear factors - In and beyond the liver. J Hepatol. 2018 May;68(5):1033-1048. doi: 10.1016/j.jhep.2017.11.026. Epub 2017 Nov 24. PMID: 29175243.\u003c/li\u003e\n\u003cli\u003eTafaleng EN, Mukherjee A, Bell A, Morita K, Guzman-Lepe J, Haep N, Florentino RM, Diaz-Aragon R, Frau C, Ostrowska A, Schultz JR, Martini PGV, Soto-Gutierrez A, Fox IJ. Hepatocyte Nuclear Factor 4 alpha 2 Messenger RNA Reprograms Liver-Enriched Transcription Factors and Functional Proteins in End-Stage Cirrhotic Human Hepatocytes. Hepatol Commun. 2021 Nov;5(11):1911-1926. doi: 10.1002/hep4.1763. Epub 2021 Jul 1. PMID: 34558820; PMCID: PMC8557308.\u003c/li\u003e\n\u003cli\u003eKhan SF, Damerell V, Omar R, Du Toit M, Khan M, Maranyane HM, Mlaza M, Bleloch J, Bellis C, Sahm BDB, Peres J, ArulJothi KN, Prince S. The roles and regulation of TBX3 in development and disease. Gene. 2020 Feb 5;726:144223. doi: 10.1016/j.gene.2019.144223. Epub 2019 Oct 26. PMID: 31669645; PMCID: PMC7108957.\u003c/li\u003e\n\u003cli\u003eMiao ZF, Liu XY, Xu HM, Wang ZN, Zhao TT, Song YX, Xing YN, Huang JY, Zhang JY, Xu H, Xu YY. Tbx3 overexpression in human gastric cancer is correlated with advanced tumor stage and nodal status and promotes cancer cell growth and invasion. Virchows Arch. 2016 Nov;469(5):505-513. doi: 10.1007/s00428-016-2007-9. Epub 2016 Aug 24. PMID: 27553355.\u003c/li\u003e\n\u003cli\u003eDouglas NC, Papaioannou VE. The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia. 2013 Jun;18(2):143-7. doi: 10.1007/s10911-013-9282-8. Epub 2013 Apr 28. PMID: 23624936; PMCID: PMC3692603.\u003c/li\u003e\n\u003cli\u003eHuang L, Shao W, Wang X, Li F, Mao W. TBX3 stimulates proliferation and stem cell self-renewal in bladder carcinoma. Histol Histopathol. 2023 Jan;38(1):65-72. doi: 10.14670/HH-18-496. Epub 2022 Jul 20. PMID: 35856500.\u003c/li\u003e\n\u003cli\u003eZhou J, Wu J, Wu G, Huang J, Zhang Y, Che J, Zhu K, Geng J, Fan Q. TBX18 knockdown sensitizes esophageal squamous cell carcinoma to radiotherapy by blocking the CHN1/RhoA axis. Radiother Oncol. 2023 Sep;186:109788. doi: 10.1016/j.radonc.2023.109788. Epub 2023 Jul 1. PMID: 37399907.\u003c/li\u003e\n\u003cli\u003eTakeichi M, Nimura K, Mori M, Nakagami H, Kaneda Y. The transcription factors Tbx18 and Wt1 control the epicardial epithelial-mesenchymal transition through bi-directional regulation of Slug in murine primary epicardial cells. PLoS One. 2013;8(2):e57829. doi: 10.1371/journal.pone.0057829. Epub 2013 Feb 28. PMID: 23469079; PMCID: PMC3585213.\u003c/li\u003e\n\u003cli\u003eBolt CC, Negi S, Guimar\u0026atilde;es-Camboa N, Zhang H, Troy JM, Lu X, Kispert A, Evans SM, Stubbs L. Tbx18 Regulates the Differentiation of Periductal Smooth Muscle Stroma and the Maintenance of Epithelial Integrity in the Prostate. PLoS One. 2016 Apr 27;11(4):e0154413. doi: 10.1371/journal.pone.0154413. Erratum in: PLoS One. 2016;11(6):e0157283. PMID: 27120339; PMCID: PMC4847854.\u003c/li\u003e\n\u003cli\u003eGorabi AM, Hajighasemi S, Tafti HA, Atashi A, Soleimani M, Aghdami N, Saeid AK, Khori V, Panahi Y, Sahebkar A. TBX18 transcription factor overexpression in human-induced pluripotent stem cells increases their differentiation into pacemaker-like cells. J Cell Physiol. 2019 Feb;234(2):1534-1546. doi: 10.1002/jcp.27018. Epub 2018 Aug 5. PMID: 30078203.\u003c/li\u003e\n\u003cli\u003eJi X, Chen X, Zhang B, Xie M, Zhang T, Luo X, Liu D, Feng Y, Wang Y, Sun M, Li C, Huang W, Xia L. T-box transcription factor 19 promotes hepatocellular carcinoma metastasis through upregulating EGFR and RAC1. Oncogene. 2022 Apr;41(15):2225-2238. doi: 10.1038/s41388-022-02249-2. Epub 2022 Feb 26. PMID: 35217793.\u003c/li\u003e\n\u003cli\u003eLi Z, Wang Y, Duan S, Shi Y, Li S, Zhang X, Ren J. Expression of TBX3 in Hepatocellular Carcinoma and Its Clinical Implication. Med Sci Monit. 2018 Dec 22;24:9324-9333. doi: 10.12659/MSM.909378. PMID: 30578408; PMCID: PMC6320639.\u003c/li\u003e\n\u003cli\u003eSuresh D, Srinivas AN, Prashant A, Harikumar KB, Kumar DP. Therapeutic options in hepatocellular carcinoma: a comprehensive review. Clin Exp Med. 2023 Oct;23(6):1901-1916. doi: 10.1007/s10238-023-01014-3. Epub 2023 Feb 13. PMID: 36780119.\u003c/li\u003e\n\u003cli\u003eLiu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, Zhou Z, Shu G, Yin G. Wnt/\u0026beta;-catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022 Jan 3;7(1):3. doi: 10.1038/s41392-021-00762-6. PMID: 34980884; PMCID: PMC8724284.\u003c/li\u003e\n\u003cli\u003eClevers H. Wnt/beta-catenin signaling in development and disease. Cell. 2006 Nov 3;127(3):469-80. doi: 10.1016/j.cell.2006.10.018. PMID: 17081971.\u003c/li\u003e\n\u003cli\u003eSteinhart Z, Angers S. Wnt signaling in development and tissue homeostasis. Development. 2018 Jun 8;145(11):dev146589. doi: 10.1242/dev.146589. PMID: 29884654.\u003c/li\u003e\n\u003cli\u003ePerugorria MJ, Olaizola P, Labiano I, Esparza-Baquer A, Marzioni M, Marin JJG, Bujanda L, Banales JM. Wnt-\u0026beta;-catenin signalling in liver development, health and disease. Nat Rev Gastroenterol Hepatol. 2019 Feb;16(2):121-136. doi: 10.1038/s41575-018-0075-9. PMID: 30451972.\u003c/li\u003e\n\u003cli\u003eHe S, Tang S. WNT/\u0026beta;-catenin signaling in the development of liver cancers. Biomed Pharmacother. 2020 Dec;132:110851. doi: 10.1016/j.biopha.2020.110851. Epub 2020 Oct 17. PMID: 33080466.\u003c/li\u003e\n\u003cli\u003eYu F, Yu C, Li F, Zuo Y, Wang Y, Yao L, Wu C, Wang C, Ye L. Wnt/\u0026beta;-catenin signaling in cancers and targeted therapies. Signal Transduct Target Ther. 2021 Aug 30;6(1):307. doi: 10.1038/s41392-021-00701-5. PMID: 34456337; PMCID: PMC8403677.\u003c/li\u003e\n\u003cli\u003eZhang Y, Wang X. Targeting the Wnt/\u0026beta;-catenin signaling pathway in cancer. J Hematol Oncol. 2020 Dec 4;13(1):165. doi: 10.1186/s13045-020-00990-3. PMID: 33276800; PMCID: PMC7716495.\u003c/li\u003e\n\u003cli\u003eChatterjee A, Paul S, Bisht B, Bhattacharya S, Sivasubramaniam S, Paul MK. Advances in targeting the WNT/\u0026beta;-catenin signaling pathway in cancer. Drug Discov Today. 2022 Jan;27(1):82-101. doi: 10.1016/j.drudis.2021.07.007. Epub 2021 Jul 10. PMID: 34252612.\u003c/li\u003e\n\u003cli\u003eZhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017 Mar;36(11):1461-1473. doi: 10.1038/onc.2016.304. Epub 2016 Sep 12. PMID: 27617575; PMCID: PMC5357762.\u003c/li\u003e\n\u003cli\u003eDeldar Abad Paskeh M, Mirzaei S, Ashrafizadeh M, Zarrabi A, Sethi G. Wnt/\u0026beta;-Catenin Signaling as a Driver of Hepatocellular Carcinoma Progression: An Emphasis on Molecular Pathways. J Hepatocell Carcinoma. 2021 Nov 25;8:1415-1444. doi: 10.2147/JHC.S336858. PMID: 34858888; PMCID: PMC8630469.\u003c/li\u003e\n\u003cli\u003eXu C, Xu Z, Zhang Y, Evert M, Calvisi DF, Chen X. \u0026beta;-Catenin signaling in hepatocellular carcinoma. J Clin Invest. 2022 Feb 15;132(4):e154515. doi: 10.1172/JCI154515. PMID: 35166233; PMCID: PMC8843739.\u003c/li\u003e\n\u003cli\u003eKhalaf AM, Fuentes D, Morshid AI, Burke MR, Kaseb AO, Hassan M, Hazle JD, Elsayes KM. Role of Wnt/\u0026beta;-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance. J Hepatocell Carcinoma. 2018 Jun 27;5:61-73. doi: 10.2147/JHC.S156701. PMID: 29984212; PMCID: PMC6027703.\u003c/li\u003e\n\u003cli\u003eWang H, Shi X. SAC3D1 activates Wnt/\u0026beta;‑catenin signalling in hepatocellular carcinoma. Mol Med Rep. 2022 Oct;26(4):317. doi: 10.3892/mmr.2022.12833. Epub 2022 Aug 25. PMID: 36004462.\u003c/li\u003e\n\u003cli\u003eAoki T, Nishida N, Kudo M. Clinical Significance of the Duality of Wnt/\u0026beta;-Catenin Signaling in Human Hepatocellular Carcinoma. Cancers (Basel). 2022 Jan 17;14(2):444. doi: 10.3390/cancers14020444. PMID: 35053606; PMCID: PMC8773595.\u003c/li\u003e\n\u003cli\u003eGhedini GC, Ronca R, Presta M, Giacomini A. Future applications of FGF/FGFR inhibitors in cancer. Expert Rev Anticancer Ther. 2018 Sep;18(9):861-872. doi: 10.1080/14737140.2018.1491795. Epub 2018 Jul 2. PMID: 29936878.\u003c/li\u003e\n\u003cli\u003eRay AT, Mazot P, Brewer JR, Catela C, Dinsmore CJ, Soriano P. FGF signaling regulates development by processes beyond canonical pathways. Genes Dev. 2020 Dec 1;34(23-24):1735-1752. doi: 10.1101/gad.342956.120. Epub 2020 Nov 12. Erratum in: Genes Dev. 2021 May 1;35(9-10):783. PMID: 33184218; PMCID: PMC7706708.\u003c/li\u003e\n\u003cli\u003eTeven CM, Farina EM, Rivas J, Reid RR. Fibroblast growth factor (FGF) signaling in development and skeletal diseases. Genes Dis. 2014 Dec 1;1(2):199-213. doi: 10.1016/j.gendis.2014.09.005. PMID: 25679016; PMCID: PMC4323088.\u003c/li\u003e\n\u003cli\u003eLeerberg DM, Hopton RE, Draper BW. Fibroblast Growth Factor Receptors Function Redundantly During Zebrafish Embryonic Development. Genetics. 2019 Aug;212(4):1301-1319. doi: 10.1534/genetics.119.302345. Epub 2019 Jun 7. PMID: 31175226; PMCID: PMC6707458.\u003c/li\u003e\n\u003cli\u003eOrnitz DM, Marie PJ. Fibroblast growth factor signaling in skeletal development and disease. Genes Dev. 2015 Jul 15;29(14):1463-86. doi: 10.1101/gad.266551.115. PMID: 26220993; PMCID: PMC4526732.\u003c/li\u003e\n\u003cli\u003eKorc M, Friesel RE. The role of fibroblast growth factors in tumor growth. Curr Cancer Drug Targets. 2009 Aug;9(5):639-51. doi: 10.2174/156800909789057006. Epub 2009 Aug 1. PMID: 19508171; PMCID: PMC3664927.\u003c/li\u003e\n\u003cli\u003eLoda A, Turati M, Semeraro F, Rezzola S, Ronca R. Exploring the FGF/FGFR System in Ocular Tumors: New Insights and Perspectives. Int J Mol Sci. 2022 Mar 30;23(7):3835. doi: 10.3390/ijms23073835. PMID: 35409195; PMCID: PMC8998873.\u003c/li\u003e\n\u003cli\u003ePresta M, Chiodelli P, Giacomini A, Rusnati M, Ronca R. Fibroblast growth factors (FGFs) in cancer: FGF traps as a new therapeutic approach. Pharmacol Ther. 2017 Nov;179:171-187. doi: 10.1016/j.pharmthera.2017.05.013. Epub 2017 May 28. PMID: 28564583.\u003c/li\u003e\n\u003cli\u003eKumar V, Goutam RS, Park S, Lee U, Kim J. Functional Roles of FGF Signaling in Early Development of Vertebrate Embryos. Cells. 2021 Aug 20;10(8):2148. doi: 10.3390/cells10082148. PMID: 34440915; PMCID: PMC8391977.\u003c/li\u003e\n\u003cli\u003eWang Y, Liu D, Zhang T, Xia L. FGF/FGFR Signaling in Hepatocellular Carcinoma: From Carcinogenesis to Recent Therapeutic Intervention. Cancers (Basel). 2021 Mar 17;13(6):1360. doi: 10.3390/cancers13061360. PMID: 33802841; PMCID: PMC8002748.\u003c/li\u003e\n\u003cli\u003eChen Z, Jiang L, Liang L, Koral K, Zhang Q, Zhao L, Lu S, Tao J. The Role of Fibroblast Growth Factor 19 in Hepatocellular Carcinoma. Am J Pathol. 2021 Jul;191(7):1180-1192. doi: 10.1016/j.ajpath.2021.04.014. Epub 2021 May 14. PMID: 34000282; PMCID: PMC8351122.\u003c/li\u003e\n\u003cli\u003eWang Y, Liu D, Zhang T, Xia L. FGF/FGFR Signaling in Hepatocellular Carcinoma: From Carcinogenesis to Recent Therapeutic Intervention. Cancers (Basel). 2021 Mar 17;13(6):1360. doi: 10.3390/cancers13061360. PMID: 33802841; PMCID: PMC8002748.\u003c/li\u003e\n\u003cli\u003eMotoo Y, Sawabu N, Nakanuma Y. Expression of epidermal growth factor and fibroblast growth factor in human hepatocellular carcinoma: an immunohistochemical study. Liver. 1991 Oct;11(5):272-7. doi: 10.1111/j.1600-0676.1991.tb00529.x. PMID: 1660093.\u003c/li\u003e\n\u003cli\u003eWang H, Yang J, Zhang K, Liu J, Li Y, Su W, Song N. Advances of Fibroblast Growth Factor/Receptor Signaling Pathway in Hepatocellular Carcinoma and its Pharmacotherapeutic Targets. Front Pharmacol. 2021 Apr 15;12:650388. doi: 10.3389/fphar.2021.650388. PMID: 33935756; PMCID: PMC8082422.\u003c/li\u003e\n\u003cli\u003eBirchmeier C, Gherardi E. Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. Trends Cell Biol. 1998 Oct;8(10):404-10. doi: 10.1016/s0962-8924(98)01359-2. PMID: 9789329.\u003c/li\u003e\n\u003cli\u003eNakamura T, Mizuno S. The discovery of hepatocyte growth factor (HGF) and its significance for cell biology, life sciences and clinical medicine. Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(6):588-610. doi: 10.2183/pjab.86.588. PMID: 20551596; PMCID: PMC3081175.\u003c/li\u003e\n\u003cli\u003eSweeney WE Jr, Avner ED. The role of hepatocyte growth factor (HGF) at progressive stages of metanephric development. In Vitro Cell Dev Biol Anim. 1998 Feb;34(2):189-94. doi: 10.1007/s11626-998-0104-z. PMID: 9542659.\u003c/li\u003e\n\u003cli\u003eQi Y, Li M, Xu L, Chang Z, Shu X, Zhou L. Therapeutic role of human hepatocyte growth factor (HGF) in treating hair loss. PeerJ. 2016 Nov 1;4:e2624. doi: 10.7717/peerj.2624. PMID: 27833804; PMCID: PMC5101615.\u003c/li\u003e\n\u003cli\u003eNakamura T, Sakai K, Nakamura T, Matsumoto K. Hepatocyte growth factor twenty years on: Much more than a growth factor. J Gastroenterol Hepatol. 2011 Jan;26 Suppl 1:188-202. doi: 10.1111/j.1440-1746.2010.06549.x. PMID: 21199531.\u003c/li\u003e\n\u003cli\u003eMulcahy EQX, Colόn RR, Abounader R. HGF/MET Signaling in Malignant Brain Tumors. Int J Mol Sci. 2020 Oct 13;21(20):7546. doi: 10.3390/ijms21207546. PMID: 33066121; PMCID: PMC7590206.\u003c/li\u003e\n\u003cli\u003eModica C, Olivero M, Zuppini F, Milan M, Basilico C, Vigna E. HGF/MET Axis Induces Tumor Secretion of Tenascin-C and Promotes Stromal Rewiring in Pancreatic Cancer. Cancers (Basel). 2021 Jul 14;13(14):3519. doi: 10.3390/cancers13143519. PMID: 34298732; PMCID: PMC8305254.\u003c/li\u003e\n\u003cli\u003eMatsumoto K, Umitsu M, De Silva DM, Roy A, Bottaro DP. Hepatocyte growth factor/MET in cancer progression and biomarker discovery. Cancer Sci. 2017 Mar;108(3):296-307. doi: 10.1111/cas.13156. PMID: 28064454; PMCID: PMC5378267.\u003c/li\u003e\n\u003cli\u003ePai P, Kittur SK. Hepatocyte growth factor: A novel tumor marker for breast cancer. J Cancer Res Ther. 2023 Apr;19(Supplement):S0. doi: 10.4103/jcrt.JCRT_1084_16. PMID: 37147943.\u003c/li\u003e\n\u003cli\u003eDing X, Xi W, Ji J, Cai Q, Jiang J, Shi M, Yu Y, Zhu Z, Zhang J. HGF derived from cancer‑associated fibroblasts promotes vascularization in gastric cancer via PI3K/AKT and ERK1/2 signaling. Oncol Rep. 2018 Aug;40(2):1185-1195. doi: 10.3892/or.2018.6500. Epub 2018 Jun 18. PMID: 29917165.\u003c/li\u003e\n\u003cli\u003eMeng W, Chen T. Association between the HGF/c‑MET signaling pathway and tumorigenesis, progression and prognosis of hepatocellular carcinoma (Review). Oncol Rep. 2021 Sep;46(3):191. doi: 10.3892/or.2021.8142. Epub 2021 Jul 19. PMID: 34278495.\u003c/li\u003e\n\u003cli\u003eZhang T, Wang Y, Xie M, Ji X, Luo X, Chen X, Zhang B, Liu D, Feng Y, Sun M, Huang W, Xia L. HGF-mediated elevation of ETV1 facilitates hepatocellular carcinoma metastasis through upregulating PTK2 and c-MET. J Exp Clin Cancer Res. 2022 Sep 16;41(1):275. doi: 10.1186/s13046-022-02475-2. PMID: 36109787; PMCID: PMC9479266.\u003c/li\u003e\n\u003cli\u003eVenepalli NK, Goff L. Targeting the HGF-cMET Axis in Hepatocellular Carcinoma. Int J Hepatol. 2013;2013:341636. doi: 10.1155/2013/341636. Epub 2013 Mar 31. PMID: 23606971; PMCID: PMC3626399.\u003c/li\u003e\n\u003cli\u003eWu MY, Hill CS. Tgf-beta superfamily signaling in embryonic development and homeostasis. Dev Cell. 2009 Mar;16(3):329-43. doi: 10.1016/j.devcel.2009.02.012. PMID: 19289080.\u003c/li\u003e\n\u003cli\u003eKitisin K, Saha T, Blake T, Golestaneh N, Deng M, Kim C, Tang Y, Shetty K, Mishra B, Mishra L. Tgf-Beta signaling in development. Sci STKE. 2007 Aug 14;2007(399):cm1. doi: 10.1126/stke.3992007cm1. PMID: 17699101.\u003c/li\u003e\n\u003cli\u003eLee JH, Massagu\u0026eacute; J. TGF-\u0026beta; in developmental and fibrogenic EMTs. Semin Cancer Biol. 2022 Nov;86(Pt 2):136-145. doi: 10.1016/j.semcancer.2022.09.004. Epub 2022 Sep 29. PMID: 36183999; PMCID: PMC10155902.\u003c/li\u003e\n\u003cli\u003eJia S, Meng A. TGF\u0026beta; family signaling and development. Development. 2021 Mar 12;148(5):dev188490. doi: 10.1242/dev.188490. PMID: 33712443.\u003c/li\u003e\n\u003cli\u003eMassagu\u0026eacute; J. TGF-\u0026beta; signaling in development and disease. FEBS Lett. 2012 Jul 4;586(14):1833. doi: 10.1016/j.febslet.2012.05.030. Epub 2012 May 28. PMID: 22651913.\u003c/li\u003e\n\u003cli\u003eSyed V. TGF-\u0026beta; Signaling in Cancer. J Cell Biochem. 2016 Jun;117(6):1279-87. doi: 10.1002/jcb.25496. Epub 2016 Feb 11. PMID: 26774024.\u003c/li\u003e\n\u003cli\u003eSabbadini F, Bertolini M, De Matteis S, Mangiameli D, Contarelli S, Pietrobono S, Melisi D. The Multifaceted Role of TGF-\u0026beta; in Gastrointestinal Tumors. Cancers (Basel). 2021 Aug 5;13(16):3960. doi: 10.3390/cancers13163960. PMID: 34439114; PMCID: PMC8391793.\u003c/li\u003e\n\u003cli\u003eKuburich NA, Sabapathy T, Demestichas BR, Maddela JJ, den Hollander P, Mani SA. Proactive and reactive roles of TGF-\u0026beta; in cancer. Semin Cancer Biol. 2023 Oct;95:120-139. doi: 10.1016/j.semcancer.2023.08.002. Epub 2023 Aug 11. PMID: 37572731; PMCID: PMC10530624.\u003c/li\u003e\n\u003cli\u003eMaruYama T, Chen W, Shibata H. TGF-\u0026beta; and Cancer Immunotherapy. Biol Pharm Bull. 2022;45(2):155-161. doi: 10.1248/bpb.b21-00966. PMID: 35110501.\u003c/li\u003e\n\u003cli\u003eChen J, Gingold JA, Su X. Immunomodulatory TGF-\u0026beta; Signaling in Hepatocellular Carcinoma. Trends Mol Med. 2019 Nov;25(11):1010-1023. doi: 10.1016/j.molmed.2019.06.007. Epub 2019 Jul 25. PMID: 31353124.\u003c/li\u003e\n\u003cli\u003eZaidi S, Gough NR, Mishra L. Mechanisms and clinical significance of TGF-\u0026beta; in hepatocellular cancer progression. Adv Cancer Res. 2022;156:227-248. doi: 10.1016/bs.acr.2022.02.002. Epub 2022 Mar 16. PMID: 35961701.\u003c/li\u003e\n\u003cli\u003eDituri F, Mancarella S, Cigliano A, Chieti A, Giannelli G. TGF-\u0026beta; as Multifaceted Orchestrator in HCC Progression: Signaling, EMT, Immune Microenvironment, and Novel Therapeutic Perspectives. Semin Liver Dis. 2019 Feb;39(1):53-69. doi: 10.1055/s-0038-1676121. Epub 2018 Dec 26. PMID: 30586675.\u003c/li\u003e\n\u003cli\u003eArrese M, Hernandez A, Astete L, Estrada L, Cabello-Verrugio C, Cabrera D. TGF-\u0026beta; and Hepatocellular Carcinoma: When A Friend Becomes An Enemy. Curr Protein Pept Sci. 2018;19(12):1172-1179. doi: 10.2174/1389203718666171117112619. PMID: 29150921.\u003c/li\u003e\n\u003cli\u003eShen Y, Wei Y, Wang Z, Jing Y, He H, Yuan J, Li R, Zhao Q, Wei L, Yang T, Lu J. TGF-\u0026beta; regulates hepatocellular carcinoma progression by inducing Treg cell polarization. Cell Physiol Biochem. 2015;35(4):1623-32. doi: 10.1159/000373976. Epub 2015 Mar 18. PMID: 25824460.\u003c/li\u003e\n\u003cli\u003eZhong Z, Jiao Z, Yu FX. The Hippo signaling pathway in development and regeneration. Cell Rep. 2024 Mar 7;43(3):113926. doi: 10.1016/j.celrep.2024.113926. Epub ahead of print. PMID: 38457338.\u003c/li\u003e\n\u003cli\u003eZheng Y, Pan D. The Hippo Signaling Pathway in Development and Disease. Dev Cell. 2019 Aug 5;50(3):264-282. doi: 10.1016/j.devcel.2019.06.003. PMID: 31386861; PMCID: PMC6748048.\u003c/li\u003e\n\u003cli\u003ePan D. The hippo signaling pathway in development and cancer. Dev Cell. 2010 Oct 19;19(4):491-505. doi: 10.1016/j.devcel.2010.09.011. PMID: 20951342; PMCID: PMC3124840.\u003c/li\u003e\n\u003cli\u003eMasliantsev K, Karayan-Tapon L, Guichet PO. Hippo Signaling Pathway in Gliomas. Cells. 2021 Jan 18;10(1):184. doi: 10.3390/cells10010184. PMID: 33477668; PMCID: PMC7831924.\u003c/li\u003e\n\u003cli\u003eYang D, Zhang N, Li M, Hong T, Meng W, Ouyang T. The Hippo Signaling Pathway: The Trader of Tumor Microenvironment. Front Oncol. 2021 Nov 11;11:772134. doi: 10.3389/fonc.2021.772134. PMID: 34858852; PMCID: PMC8632547.\u003c/li\u003e\n\u003cli\u003eXiao Y, Dong J. The Hippo Signaling Pathway in Cancer: A Cell Cycle Perspective. Cancers (Basel). 2021 Dec 10;13(24):6214. doi: 10.3390/cancers13246214. PMID: 34944834; PMCID: PMC8699626.\u003c/li\u003e\n\u003cli\u003eLi HL, Li QY, Jin MJ, Lu CF, Mu ZY, Xu WY, Song J, Zhang Y, Zhang SY. A review: hippo signaling pathway promotes tumor invasion and metastasis by regulating target gene expression. J Cancer Res Clin Oncol. 2021 Jun;147(6):1569-1585. doi: 10.1007/s00432-021-03604-8. Epub 2021 Apr 17. PMID: 33864521.\u003c/li\u003e\n\u003cli\u003eLiu Y, Wang X, Yang Y. Hepatic Hippo signaling inhibits development of hepatocellular carcinoma. Clin Mol Hepatol. 2020 Oct;26(4):742-750. doi: 10.3350/cmh.2020.0178. Epub 2020 Sep 28. PMID: 32981290; PMCID: PMC7641559.\u003c/li\u003e\n\u003cli\u003eMa J, Huang X. Research progress in role of Hippo signaling pathway in diagnosis and treatment for hepatocellular carcinoma. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2021 Jun 28;46(6):637-643. English, Chinese. doi: 10.11817/j.issn.1672-7347.2021.200243. PMID: 34275933; PMCID: PMC10930194.\u003c/li\u003e\n\u003cli\u003eChang YS, Chou YP, Chung CC, Lee YT, Yen JC, Jeng LB, Chang JG. Molecular Classification of Hepatocellular Carcinoma Using Wnt-Hippo Signaling Pathway-Related Genes. Cancers (Basel). 2022 Sep 21;14(19):4580. doi: 10.3390/cancers14194580. PMID: 36230503; PMCID: PMC9559216.\u003c/li\u003e\n\u003cli\u003eZheng T, Wang J, Jiang H, Liu L. Hippo signaling in oval cells and hepatocarcinogenesis. Cancer Lett. 2011 Mar 28;302(2):91-9. doi: 10.1016/j.canlet.2010.12.008. Epub 2011 Jan 17. PMID: 21247686.\u003c/li\u003e\n\u003cli\u003eShi X, Zhu HR, Liu TT, Shen XZ, Zhu JM. The Hippo pathway in hepatocellular carcinoma: Non-coding RNAs in action. Cancer Lett. 2017 Aug 1;400:175-182. doi: 10.1016/j.canlet.2017.04.032. Epub 2017 Apr 29. PMID: 28461246.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Sindh Medical College - Jinnah Sindh Medical University / Dow University of Health Sciences, Karachi, Pakistan","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hepatocellular carcinoma, Heterogeneity, Transdifferentiation, Hepatocyte-specific genes, Transcription factors, Signaling pathways, Tumor microenvironment, Therapeutic targets","lastPublishedDoi":"10.21203/rs.3.rs-4360926/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4360926/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003eHepatocellular carcinoma (HCC) presents challenges due to tumor heterogeneity and therapeutic resistance. Understanding the molecular mechanisms driving heterogeneity is crucial. Key transcription factors (HNF4A, HNF1A, FOXA1/2, etc.) and signaling pathways (Wnt/β-catenin, FGF, HGF, etc.) are dysregulated in HCC. Dysregulation disrupts hepatocyte genetic programming, leading to heterogeneous cell populations. Investigating these mechanisms offers insights for targeted therapies and improving patient outcomes in HCC.\u003c/p\u003e\u003ch2\u003eMethods:\u003c/h2\u003e \u003cp\u003eDatabases, including PubMed, MEDLINE, Google Scholar, and open access/ subscription-based journals were searched for published articles without any date restrictions, to trace the emergence of HCC heterogeneity by investigating the hepatocyte-specific genes/TFs/signaling pathways across cellular and tumor landscapes. Based on the criteria mentioned in the methods section, studies were systematically reviewed to investigate HCC Heterogeneity. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).\u003c/p\u003e\u003ch2\u003eResults:\u003c/h2\u003e \u003cp\u003eThis study into hepatocellular carcinoma (HCC) revealed dysregulation of key transcription factors (TFs) and signaling pathways. Transcription factors HNF4A, HNF1A, FOXA1/2, CEBPA, GATA4/6, PROX1, SOX9, HNF6/Onecut1, and ONECUT2/HNF6β showed altered expression patterns, disrupting hepatocyte genetic programming and promoting heterogeneous cell populations in HCC. Dysregulated Wnt/β-catenin, FGF, HGF, TGF-β, and Hippo signaling pathways influenced cellular fate decisions and interactions with the tumor microenvironment, further contributing to HCC heterogeneity. Dysregulated NOTCH signaling and TBX3/18 transcription factors highlighted the complexity of HCC heterogeneity. This study points to the critical role of dysregulated TFs and signaling pathways in driving HCC heterogeneity and transdifferentiation, providing insights for targeted therapeutic interventions to improve patient outcomes.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eThe decline in the gene expression of hepatocyte cell type-specific genes dysregulates the genetic programing of hepatocytes involved in cell type-specific homeostasis. The multiple roles of every gene/TF begin to manifest themselves causing the emergence of heterogeneity. The dysregulation of hepatocyte-specific genes and signaling pathways in hepatocellular carcinoma (HCC) disrupts cellular homeostasis, leading to the emergence of heterogeneity and transdifferentiation. Key transcription factors like HNF4A, HNF1A, and FOXA1/2, along with pathways such as Wnt/β-catenin and Hippo signaling, play crucial roles. This disruption sets the stage for diverse cellular phenotypes within the tumor microenvironment. Understanding these molecular mechanisms is vital for developing targeted therapeutic strategies to address HCC heterogeneity and improve patient outcomes.\u003c/p\u003e","manuscriptTitle":"Mapping Heterogeneity of Hepatocellular Carcinoma by Investigating Hepatocyte-Specific Genes/TFs/Pathways Across Cellular and Tumor Landscapes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-07 16:47:04","doi":"10.21203/rs.3.rs-4360926/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cde3cc2b-c042-4fb6-9517-332081fc4b46","owner":[],"postedDate":"May 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":31452094,"name":"Gastroenterology \u0026 Hepatology"},{"id":31452095,"name":"Oncology"},{"id":31452096,"name":"Stem Cell \u0026 Developmental Cell Biology"},{"id":31452097,"name":"Medical Genetics"}],"tags":[],"updatedAt":"2024-05-07T16:47:04+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-07 16:47:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4360926","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4360926","identity":"rs-4360926","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}