A comprehensive bioinformatics analysis of THOC3 highlights its potential role in pan-cancer and clinical significance in lung adenocarcinoma

A comprehensive bioinformatics analysis of THOC3 highlights its potential role in pan-cancer and clinical significance in lung adenocarcinoma | 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 A comprehensive bioinformatics analysis of THOC3 highlights its potential role in pan-cancer and clinical significance in lung adenocarcinoma Jixin Zhang, Qi Zhao, Jidong Zhao, Xing Cui, Xin Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4419605/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 THOC3, a crucial component of the THO complex, is involved in mRNA biosynthesis and export. Studies have shown that dysregulation of THOC3 is linked to various aspects of tumorigenesis, including tumor initiation, progression, and metastasis. In this study, we utilized a comprehensive bioinformatics analysis to explore the role of THOC3 in different types of cancer. Our analysis of different types of data helped us understand how THOC3 contributes to cancer at the molecular level, and its clinical significance. Moreover, our immune analysis revealed notable correlations between THOC3 and multiple immune-related signaling pathways. Our findings highlight the potential oncogenic role of THOC3 across different types of cancer and propose dysregulation of THOC3 as a key driver in tumor development. Furthermore, the associations between THOC3 and immune-related signaling pathways indicate its potential as a target for further experimental validation and investigation in the realm of immunotherapy. THOC3 pan-cancer prognosis immune cell infiltration Drug Sensitivity Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 1.0: Introduction Cancer, influenced by factors like geographical distribution, lifestyle habits, genetics, and economic status, remains a leading cause of premature death globally [3] . Research anticipates a noteworthy rise in the prevalence of cancer patients in the upcoming decades, predominantly in low- and middle-income nations [1, 2] . In cancer progression, gene expression transcription plays a critical role, with normal transcription processes being initiated and sustained by master transcription factors [5] . These master transcription factors interact with DNA enhancer elements, recruiting co-activators and transcription machinery to regulate gene expression [6] . Therefore, investigating the fundamental mechanisms of tumors, identifying key transcription factors in cancer patients, and discovering new therapeutic targets are of particular urgency. The THO complex (THOC), primarily comprising six subunits (THOC1~3 and THOC5~7), functions via the TREX complex within cells. This complex is integral to transcription, mRNA processing, export, DNA damage prevention, embryonic development, and cell differentiation in specific adult tissues [4 ,7, 8] . Research has demonstrated that dysregulation of the THO complex is intricately linked to cancer, particularly influencing cell cycle regulation, DNA repair, and replication processes that contribute to cancer cell invasiveness, treatment resistance, and adverse patient outcomes [9 - 14] . The overexpression of THOC1 and THOC2 is associated with abnormal proliferation rates and cell cycle regulation in various cancers [15 - 18] ; THOC5 plays a critical role in RNA 3' end processing and cell differentiation and is also associated with the formation of certain leukemias and solid tumors [19 ,20] ; Extensive research has substantiated that the involvement of THOC7 contributes to the advancement of cutaneous squamous cell carcinoma, emphasizing its role in disease progression [21] . Aberrant expression of the THO complex may lead to imbalance in intracellular information transmission, affecting normal cell growth and death processes. Recent research has progressively uncovered THOC3's role in cancer development , McCormack NM and colleagues demonstrated that silencing the THOC3 gene markedly increases SMN protein levels, which regulate RNA metabolism and are closely linked to cell migration, invasion, and adhesion [22 ,23] . Yu T and colleagues discovered that elevated THOC3 expression leads to an increase in PFKFB4 levels, which consequently enhances glycolysis and facilitates the progression and motility of LUSC cells [24] . Additionally, research has suggested that the association of THOC3 with RNA-binding proteins (RBPs) holds potential as a prognostic indicator for patients with glioblastoma [25] . Nevertheless, the precise expression pattern and regulatory mechanism of THOC3 in various types of cancer remain uncertain within the academic community. This emphasizes the significance of conducting further investigations on the involvement of the THOC family in cancer. Exploring the impact of THOC3 in pan-cancer is urgently needed to improve patient prognosis. In this investigation, we carried out a comprehensive assessment of the association between THOC3 expression, its prognostic value, DNA alterations, and its implications across various types of cancer. This was achieved by integrating data from various databases and employing diverse bioinformatics methodologies. Additional analysis was conducted to investigate the correlation between THOC3 expression and the immune microenvironment in tumor tissues. A significant positive correlation was observed between THOC3 expression and pro-tumorigenic cells, which could result in inferior outcomes for patients with high levels of THOC3. These findings indicate that targeting THOC3 might offer a promising strategy for cancer therapy in the future. 2.0 Materials and Methods 2.1 Analysis of THOC3 expression in various tumors. TIMER 2.0 ( http://timer.cistrome.org/ ) is a resource primarily focused on analyzing gene expression differences in tumors [ 26 ] . It enables researchers to estimate tumor immune infiltration using gene expression data, providing valuable insights into the molecular alterations in the tumor microenvironment. Given the absence of normal tissue controls for some tumors in TIMER 2.0, we sourced corresponding transcriptome data from the UCSC Xena database. Sangerbox ( http://SangerBox.com ) is a tool for analyzing gene expression differences in tumors, aiding cancer research [ 27 ] . Additionally, Using the UALCAN database, we explored THOC3's expression levels, phosphorylation status, and promoter methylation in various cancers [ 28 ] . Finally, The Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database ( http://gepia2.cancer-pku.cn/ ) is a useful tool for analyzing the correlation between gene expression and clinical information, including tumor staging in various types of cancer [ 29 ] . 2.2 Prognostic Analysis of THOC3 in Pan-Cancer The Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database ( http://gepia2.cancer-pku.cn/ ) is a powerful tool for studying the correlation between THOC3 gene expression and cancer patient survival time. It provides insights into the prognostic significance of THOC3 across various types of cancer. We categorized individuals into groups of high and low expression based on the median expression level of the THOC3 gene. Next, we employed the Kaplan-Meier approach to generate overall survival (OS) and disease-free survival (DFS) curves for both high and low THOC3 expression groups in the context of 33 cancer types. Finally, to compare survival between the two groups, we utilized the log-rank test. 2.3THOC3 Variation Analysis cbioportal ( https://www.cbioportal.org/ ) is a tool for analyzing genomic alterations to understand molecular features of tumors [ 30 ] . This platform has functionalities for analyzing gene mutation frequencies, mutation types (including mutations, amplifications, and multiple mutations), as well as mutation sites. In our study, we utilized this database to conduct a variation analysis of THOC3. 2.4 Immunological Checkpoint Analysis of THOC3 The expression data of THOC3 gene and 60 selected immune checkpoint pathway genes were analyzed in various samples from the UCSC database ( https://xenabrowser.net/ ) [ 31 ] . We filtered out samples with expression levels of 0 and all normal samples. We transformed expression values using log2(x + 1), then calculated Pearson correlations between THOC3 and immune pathway marker genes. Additionally, Through the TIDE database ( http://tide.dfci.harvard.edu ), we further investigated the significant correlation between THOC3 and PD1 as well as CTLA4 [ 32 , 33 ] . 2.5 Immunological Correlation Analysis We standardized the TCGA pan-cancer dataset from UCSC and transformed gene expression values using log2(x + 1) [ 27 ] . Subsequently, we mapped tumor gene expression profiles to GeneSymbol and evaluated immune scores using the deconvo_xCell method from the R package IOBR, while also examining the relationship between THOC3 and Th2 cells. 2.6 Relationship between THOC3 and TMB, MSI, HRD Using the SangerBox tool, we retrieved a pan-cancer dataset from the UCSC Xena database ( https://xenabrowser.net/ ) that had undergone uniform standardization. Within this dataset, we integrated TMB (tumor mutation burden) alongside gene expression data derived from the samples. To enhance the sensitivity of data analysis, we performed a logarithmic transformation on each gene expression value, specifically log2(x + 1). Additionally, we excluded single cancer types with sample sizes less than 3 to guarantee the validity and dependability of statistical analysis.Finally, we calculated the Pearson correlation between THOC3 gene expression and tumor mutation burden (TMB), microsatellite instability (MSI), and homologous recombination deficiency (HRD) to explore the potential associations between these biomarkers and THOC3 expression. 2.7 THOC3 Single Cell Functional Analysis and Gene Function Enrichment Analysis CancerSEA( http://biocc.hrbmu.edu.cn/CancerSEA/ ) is a platform for analyzing cancer cell functions at the single-cell level [ 34 ] . It is instrumental in studying the single-cell functional roles of THOC3 in cancer. GeneMANIA ( http://genemania.org/ ) is a freely accessible database and analysis tool that predicts gene functional associations by integrating diverse data sources [ 35 ] . It is utilized to identify the top 20 genes most correlated with THOC3 expression. The DAVID database ( http://david.abcc.ncifcrf.gov/ ) is a bioinformatics resource offering comprehensive functional annotation for large-scale gene or protein lists [ 36 ] . It facilitates functional enrichment analysis, including Gene Ontology (GO) analysis for biological processes, cellular components(CC), and molecular functions(MF). Additionally, it conducts pathway analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases, aiding in exploring THOC3 functional enrichment. 2.8 Correlation Analysis of THOC3 Expression and Drug Sensitivity The CellMiner database ( https://discover.nci.nih.gov/cellminer/home.do ) is a resource for investigating relationships between gene expression, including THOC3, and drug sensitivity. It provides RNA-seq expression data, drug activity information, and facilitates the selection of clinically tested and FDA-approved drugs for analysis using R packages like 'limma,' 'impute,' 'ggpubr,' and 'ggplot2'. 2.9 The critical role of EMC6 in LUAD We downloaded LUAD data from the UCSC database, and finally obtained 515 tumor samples and 59 normal tissue samples. We conducted differential analysis, survival analysis, prognosis analysis, and GSEA analysis on them. We selected four groups of human lung adenocarcinoma and adjacent normal specimens from the thoracic surgery department of the Fourth Hospital of Hebei Medical University for Western blot analysis and semi-quantitative evaluation of IHC. Using GAPDH protein as an internal reference, the results verified the significantly high expression of THOC3 protein in LUAD. 3.0 Results 3.1 Analysis of THOC3 Expression Levels in Various Cancer Tissues This study meticulously analyzed THOC3 mRNA expression, revealing pronounced upregulation in 13 cancers: BLCA,BRCA, CESC,COAD,CHOL,ESCA,HNSC,LIHC,LUAD,LUSC,READ, STAD,UCEC. In contrast, it was downregulated in KICH(Fig. 1A). Due to the limited availability of normal samples in the TCGA database, we integrated data from both TCGA and GTEx databases. This allowed us to assess the variability in THOC3 expression across 34 cancer types, ensuring a comprehensive analysis(Fig. 1B). Moreover, the UALCAN database helped us determine THOC3 protein expression levels in LUAD、LUSC、OV、COAD、GBM、KIRC and LIHC, all of which showed high expression(Fig. 1C). Furthermore, we utilized the GEPIA2 database to investigate the correlation between THOC3 expression levels and disease staging, revealing significant associations in SKCM, KIRP, TGCT, and COAD (p < 0.05, Fig. 1D). 3.2Prognostic Value of THOC3 Across Cancers This study thoroughly assessed the impact of THOC3 expression levels on prognosis across 33 cancer types. In the overall survival (OS) analysis, high THOC3 expression was found to be significantly associated with shorter survival times in BRCA, LIHC, LGG, LUAD, and PAAD samples. Conversely, low THOC3 expression is associated with shorter survival times in KIRC and CESC (p < 0.05, Fig. 2A). In the disease-free survival (DFS) analysis, elevated THOC3 expression was pinpointed as a risk factor for shorter DFS in KICH, KIRP, PAAD, and SKCM (p < 0.05, Fig. 2B). 3.3 DNA Mutation Analysis Utilizing the cBioPortal database, this study conducted a comprehensive analysis of THOC3 gene mutations across a spectrum of cancers. It was found that amplification is the primary mutation type for the THOC3 gene, occurring most frequently at 33.75% in pancreatic neuroendocrine tumors. Notably, papillary gastric adenocarcinoma and uterine serous carcinomas exhibited significant amplification rates of 10% each, while renal clear cell carcinoma displayed a rate of 9.01% (Fig. 3). Furthermore, oral squamous cell carcinoma and head and neck squamous cell carcinoma primarily exhibited deep deletions, with frequencies of 7.69% and 2.33%, respectively. 3.4 Analysis of THOC3 Expression in Multiple Cancers and Its Relationship with Immune Checkpoint (ICP) Genes. In a variety of cancer types, THOC3 expression consistently correlates positively with immune checkpoint (ICP) genes, observed in cancers including LAML, KICH, KIPAN, KIRC, OV, and PAAD; in contrast, a negative correlation is evident in LUSC and THCA. More than 90% of cases involving the ICP genes CD276, VEGFA, and HMGB1 show a correlation with THOC3 expression (Fig. 4). These observations imply that elevated THOC3 expression could predict the effectiveness of immune therapies targeting ICP genes. Additionally, analysis using the TIDE database examined the link between ICB therapy responses and THOC3 expression levels. According to a 2017 PD1 cohort study by Riaz, high THOC3 expression correlates with reduced overall survival (OS) in melanoma (SKCM) patients; a 2019 study by Gide on PD1+CTLA4 indicated that elevated THOC3 expression is linked to decreased progression-free survival (PFS) in melanoma cases (Fig. 5). 3.5 Analysis of THOC3's Association with Immune Cell Profiles and Th2 Cells in Various Cancers Based on the findings depicted in Figure 6, a positive correlation is evident between THOC3 expression and pro-oncogenic immune cells, including Th2 cells, common lymphoid progenitors (CLP), megakaryocytic-erythroid progenitors (MEP), osteoblasts, and vascular smooth muscle cells (VSMC). Conversely, THOC3 expression shows a negative correlation with immune cells known for their anti-tumor activity, such as CD8+ T cells, monocytes, macrophages, and Th1 cells. Th2 cells, a type of auxiliary T cell, play a significant role in the progression and severity of tumors. This study employed the CIBERSORT technique to examine the correlation between THOC3 and Th2 cells across a broad spectrum of cancers. Research indicates that heightened THOC3 expression correlates with augmented infiltration of Th2 cells in certain cancers, including BRCA, BLCA, COADREAD, COAD, DLBC, ESCA, GBMLGG, HNSC, KICH, KIPAN, KIRC, KIRP, LGG, LIHC, LUAD, LUSC, PAAD, PRAD, READ, SARC, SKCM, SKCM-M, STAD, STES, THCA, and UVM. On the other hand, in ovarian cancer (OV) and thyroid carcinoma (THCA), high THOC3 expression significantly reduces Th2 cell infiltration (p < 0.05, Figure 7). 3.6 Exploring the Interactions Between THOC3 and Genetic Markers of Cancer Susceptibility: TMB, MSI, and HRD This study delved into the correlations between THOC3 expression and key genetic markers in oncology, namely TMB, MSI and HRD, across diverse tumor types. Notably, THOC3 demonstrated a noteworthy positive correlation with TMB in various cancers, including GBM, GBMLGG, LUAD, STES, STAD, PRAD, MESO, READ, and PCPG, but exhibited a negative correlation in LUSC (Figure 8A). Furthermore, THOC3 expression displayed a positive correlation with MSI in STES, SARC, and STAD, while exhibiting a negative correlation in GBMLGG, KIPAN, and PRAD (Figure 8B). Moreover, an analysis of HRD was conducted to further explore how THOC3 expression influences resistance to platinum-based chemotherapy treatments. The findings revealed that THOC3 significantly positively correlates with HRD in a range of cancers, including GBM, LUAD, BRCA, ESCA, STES, SARC, KIRP, KIPAN, PRAD, HNSC, KIRC, LUSC, LIHC, OV, and KICH (Figure 8C). 3.7 Single-cell functional enrichment analysis of the THOC3 In this investigation, we conducted single-cell functional enrichment analysis of the THOC3 gene across various cancer types, including AML, LUAD, OV, RCC, BRCA, HNSCC, RB, and UM (Figure 9A). Our examination, facilitated by the CancerSEA database, revealed significant associations between THOC3 expression and diverse cellular functions within each cancer context. Specifically, in AML, THOC3 expression exhibited a positive correlation with gene silencing and metastasis. Within HNSCC, THOC3 expression correlated positively with cell stemness and gene silencing, while showing a negative correlation with angiogenesis. Conversely, in BRCA, THOC3 expression was positively linked with DNA repair functionality. Notably, in OV, THOC3 expression displayed a negative correlation with tumor cell invasion. Similarly, in UM, THOC3 displayed negative associations with cell apoptosis, DNA damage, and DNA repair processes. In LUAD, THOC3 expression exhibited positive correlations with the cell cycle, DNA damage, and DNA repair, while showing negative correlations with inflammatory processes. Finally, in RB, THOC3 expression exhibited positive correlations with angiogenesis, cell differentiation, and inflammatory processes, while displaying negative correlations with DNA repair, cell cycle, and DNA damage processes (Figure 9B). 3.8 Functional Enrichment Analysis of THOC3 We utilized the GeneMANIA database to extract the top 20 genes that exhibited the strongest correlation with THOC3 (Figure 10A). Following, we performed an in-depth analysis of the potential biological functions and pathways linked to THOC3 and these 20 interacting genes utilizing the DAVID database. The enrichment analysis for biological processes (BP) demonstrated that THOC3-related genes were predominantly involved in RNA splicing, mRNA processing, mRNA nuclear export, and the export of viral mRNA from the host cell nucleus (Figure 10B). The enrichment analysis for molecular functions (MF) indicated that THOC3 was involved in protein binding, RNA binding, and mRNA binding (Figure 10C). In the enrichment analysis for cellular components (CC), THOC3-related genes were found to be enriched in the nucleoplasm, cytoplasm, and nucleolus (Figure 10D). Additionally, KEGG pathway analysis revealed the involvement of THOC3 in nucleocytoplasmic transport and spliceosome pathways (Figure 10E). 3.9 Drug Sensitivity Analysis Employing the CellMiner database, we investigated the Pearson correlation between THOC3 expression levels and drug sensitivity. The results indicate a positive correlation between the sensitivity of Allopurinol, Cladribine, Fludarabine, Bisacodyl (the active ingredient of Viraplex), Amuvatinib, Cpd-401, Econazole Nitrate, ARTENIMOL, artesunate, and the expression level of THOC3. Conversely, the sensitivity of WORTMANNIN, Depsipeptide, RAF-265, Cediranib, and Pluripotin is negatively correlated with the expression level of THOC3 (Figure 11). These results indicate a noteworthy negative correlation between THOC3 expression and the sensitivity to Pluripotin and RAF-265. 3.10 Differential Analysis and Immunological Analysis of THOC3 in Lung Adenocarcinoma To investigate the role of THOC3 further, we conducted a comparative analysis of THOC3 protein expression between tumor tissues and normal tissues. The results illustrated in Figure 12A demonstrate a notably elevated expression of THOC3 in tumor tissues relative to normal tissues, with significant disparities observed particularly in LUAD tissues. Through univariate COX regression analysis, we established that THOC3 significantly impacts the prognosis of LUAD patients and can function as an independent prognostic indicator for LUAD (Figure 12B). Furthermore, the correlation between THOC3 expression and 1-year, 3-year, and 5-year overall survival rates (OS) was examined using ROC curves, yielding area under the curve (AUC) values of 0.70, 0.71, and 0.73, respectively. These results reinforce the crucial role of elevated THOC3 expression in predicting unfavorable prognosis among LUAD patients (Figure 12C).. Our gene set enrichment analysis (GSEA) revealed that THOC3 significantly influences tumor transcription imbalance, chemokine signaling pathways, and axon guidance, as depicted in Figure 12D. These findings suggest the potential involvement of THOC3 in the pathogenesis of lung adenocarcinoma. To validate the disparities in THOC3 expression between tumor tissues and normal tissues, we analyzed four sets of human lung adenocarcinoma and adjacent normal specimens obtained from the Department of Thoracic Surgery, Fourth Affiliated Hospital of Hebei Medical University. Immunoblot analysis and semi-quantitative immunohistochemical scoring confirmed the substantial overexpression of THOC3 in lung adenocarcinoma (Figure 12E, F, G). The observed overexpression of THOC3 in tumors strengthens its potential as a novel target for treating LUAD. 4.0 Discussion In recent years, with the advancement of personalized medicine, notably the swift evolution of targeted therapy and immunotherapy, substantial strides have been achieved in cancer treatment, enhancing the outcomes for individuals facing advanced or metastatic cancer [37] . However, overall clinical outcomes remain unsatisfactory. The challenge of treating advanced cancer has prompted researchers to explore the underlying mechanisms driving cancer growth, aiding in the identification of effective therapeutic targets. Transcription refers to the process of genetic information flowing from DNA to RNA, with the cell's transcription program established and maintained by master transcription factors [5] . Cancer development is closely associated with transcriptional regulation within cells, and aberrant transcription factors are considered potential breakthroughs in cancer therapy [38] . The THOC3 gene, located on chromosome 5, encodes a protein that is a highly conserved part of the TREX complex. THOC3 plays a crucial regulatory role in splicing and recruitment during transcription, and it is also an important factor in regulating RNA-binding proteins (RBPs), as confirmed by existing research [22 ,39, 40] . Currently, research on THOC3 in cancer is limited to a few specific types of cancer, such as lung squamous cell carcinoma and glioma, with no studies yet addressing THOC3 in various cancer types. In our study, we found that THOC3 is also involved in processes such as DNA damage repair, cell death, angiogenesis, and tumor immune infiltration. Therefore, THOC3 may serve as a promising biomarker. In this investigation, we meticulously analyzed the data from the TCGA dataset to assess THOC3 expression across diverse tissue types. Our findings revealed a significant upregulation of THOC3 expression across multiple cancer types, with the exception of TGCT and KICH. Recognizing the potential discrepancies between protein and mRNA expression levels due to post-transcriptional modifications, we further scrutinized THOC3 protein expression in diverse cancer types. Our analysis unveiled a notable increase in THOC3 protein levels in cancers such as LUAD, LUSC, OV, COAD, GBM, and LIHC. Additionally, empirical evidence corroborated significant overexpression of THOC3 in LUAD. Our results underscore the significant association between THOC3 expression and cancer staging in SKCM, KIRP, TGCT, and COAD, encompassing clinical stages. Furthermore, both overall survival (OS) and disease-free survival (DFS) analyses exhibited a pronounced correlation between THOC3 expression and cancer patient prognosis. Specifically, high THOC3 levels were associated with shorter overall survival in BRCA, LGG, LIHC, LUAD, and PAAD, while showing a positive correlation with longer survival in CESC and KIRC. In terms of DFS, elevated THOC3 expression correlated with reduced disease-free survival in KICH, KIRP, PAAD, and SKCM. These results emphasize the critical importance of THOC3 in prognostic evaluations, establishing it as a dependable prognostic indicator for cancer. Mutations in genes and aberrant DNA methylation are recognized as critical factors that disrupt gene expression in cancers, markedly influencing both the onset and progression of the disease. Such genetic alterations predominantly affect key cellular processes including proliferation, apoptosis, and repair mechanisms [41, 42] . Typically, genetic changes associated with cancer manifest as point mutations, deletions, or chromosomal rearrangements. Nevertheless, in various cancer types, the THOC3 gene primarily exhibits its oncogenic potential through gene amplification [43] .This occurrence involves a notable rise in the gene's copy numbers, resulting in the excessive production of its protein. Consequently, this heightened production significantly enhances the growth and viability of cancerous cells [44] . Immunotherapy has demonstrated remarkable effectiveness in various solid tumors, representing a significant breakthrough in cancer treatment. However, the clinical remission rates are still relatively modest, underscoring the urgency for more refined and targeted immunotherapeutic strategies [45] . The tumor microenvironment (TME) constitutes a critical nexus for tumor proliferation and the invasion by immune and stromal cells. In our comprehensive study examining THOC3 expression across 39 cancer types, we observed a strong association between THOC3 expression and cell subgroups that support tumor development, such as Th2 cells, common lymphoid progenitors, myeloid-erythroid progenitors, osteoprogenitors, and vascular smooth muscle cells. Conversely, THOC3 expression is significantly inversely correlated with cytotoxic cells such as CD8+ T cells, monocytes, macrophages, and Th1 cells, which are involved in suppressing tumor progression. Notably, Th2 cells, often linked with promoting tumor progression, also contribute to angiogenesis and suppress the cellular mechanisms responsible for tumor cell elimination. Thus, THOC3 may play a crucial role in enabling tumor cells to evade immune surveillance and destruction, potentially enhancing tumor-associated angiogenesis [46, 47] . Furthermore, our findings demonstrate a significant positive correlation between THOC3 and key immune checkpoint genes, namely CD276, VEGFA, VEGFB, CD274, and HMGB1. These correlations offer novel perspectives on the role of THOC3 in the manipulation of immune checkpoint pathways pathways, paving the way for the development of innovative immune checkpoint inhibitors. Tumor mutational burden (TMB) and microsatellite instability (MSI) have been firmly established as robust biomarkers for the prognosis of various cancers and as indicators of the efficacy of several tumor immunotherapies [28] . High levels of TMB and MSI in tumors have been associated with a more favorable response to immunotherapy [48 ,50] . Through our analysis, we found a robust positive correlation between THOC3 and TMB in various tumor types, particularly in cases of LUSC. Moreover, in STES and STAD, THOC3 expression is significantly associated with both TMB and MSI, implying that high THOC3 expression could confer enhanced survival benefits post-immunotherapy in these contexts. Additionally, homologous recombination deficiency (HRD) is closely linked with increased sensitivity to platinum-based chemotherapy and PARP inhibitors, with THOC3 showing significant correlations with HRD across 15 tumor types [49] . This observation suggests that STES patients, who exhibit substantial correlations with TMB, MSI, and HRD, might achieve superior outcomes with a therapeutic regimen combining immunotherapy and PARP inhibitors. Consequently, THOC3 emerges as a promising new target for anticancer immunotherapy strategies. Utilizing the CancerSEA platform, we conducted an exhaustive pan-cancer functional evaluation of THOC3. Our single-cell functional investigations unveiled a significant positive relationship between THOC3 and DNA damage as well as metabolic processes, while demonstrating a distinct inverse association with DNA repair mechanisms in certain cancer types. These findings emphasize THOC3's critical role in regulating gene expression stability and modulating cellular stress responses in cancer cells. Emerging research has indicated that suppression of THOC3 expression in LUSC significantly reduces levels of cell cycle-associated proteins and curtails tumor cell migration [24] . Functional enrichment analysis underscores THOC3's primary engagement in cell cycle regulation, DNA transcription, and protein stability across diverse cancers, consistent with previous research [51] . Furthermore, drug sensitivity testing has demonstrated that agents such as Pluripotin and RAF-265 effectively suppress THOC3 expression. These insights not only affirm THOC3's fundamental role in the survival and motility of cancer cells but also accentuate its potential as a promising therapeutic target. Continued investigations into THOC3 as an emerging drug target are paving new paths for cancer therapy. While the impact of THOC3 in pan-cancer has been described, it is important to note some limitations. Firstly, all analyses are based on bioinformatics, and THOC3 expression has only been confirmed in lung adenocarcinoma through Western blot (WB) and immunohistochemistry (IHC). Secondly, our study did not investigate the molecular mechanism of THOC3 in cancer. Therefore, it is essential to conduct further research to explore the expression mechanism of THOC3 in tumors in future studies. Conclusion Based on this study and related online data, THOC3 is identified as playing a pivotal, multifunctional role in tumor progression. It regulates critical pathways like gene expression stability, cell cycle, and DNA transcription, impacting tumor cell survival and migration. THOC3's involvement with immune regulation and tumor microenvironment also provides new directions for cancer therapy. Understanding THOC3's molecular mechanisms in cancer is crucial, as it helps enhance its potential as a therapeutic target and prognostic biomarker, thereby improving cancer treatment strategies. Nonetheless, further research is essential to fully elucidate THOC3's action mechanisms and its potential clinical applications. Declarations AUTHOR CONTRIBUTIONS Jixin Zhang performed bioinformatics analysis and completed the manuscript. All authors gave final approval to the manuscript. ACKNOWLEDGMENTS The datasets for this study can be found in the public databases TCGA, GTEx, DAVID,CellMiner, GEPIA2,CancerSEA,Sangerbox and cBioportal. Funding: This research received no external funding. 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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-4419605","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":306379050,"identity":"6ba03734-9f8d-4f76-9ebd-58c90fdc9443","order_by":0,"name":"Jixin Zhang","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jixin","middleName":"","lastName":"Zhang","suffix":""},{"id":306379051,"identity":"ba15d5cf-d75c-4084-a7d7-cc4958670ccd","order_by":1,"name":"Qi Zhao","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Qi","middleName":"","lastName":"Zhao","suffix":""},{"id":306379052,"identity":"9fa94f24-87da-4e88-bbb9-780dc2337535","order_by":2,"name":"Jidong Zhao","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jidong","middleName":"","lastName":"Zhao","suffix":""},{"id":306379053,"identity":"2fa323da-d0ca-4f42-b01e-94ec9bedcb2b","order_by":3,"name":"Xing Cui","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Xing","middleName":"","lastName":"Cui","suffix":""},{"id":306379055,"identity":"2bde632c-9efc-4d44-9dda-b48e4a626bd9","order_by":4,"name":"Xin Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1ElEQVRIiWNgGAWjYBACNvbmA4f/8EjIycs/PkCcFj6eY4kPeGRsjA0b0hKI0yIn4WNswGOTlthwIMeASIdJMJhJSOQcTmxsOPPxxhsGOzndBkJapBvSJAzOHDZuZ+zdbDmHIdnY7AAhLTIHjkkk9hyWbWzm3SbNw3AgcRtBLRKJbRIH/x1mbDjG84xYLcnMhg08aYoNZ3jYiNTCc4zxMQMPMJBnsBlbzjEgwi/y7f0fDjOAolKC+eGNNxV2cgS1oAAJHiKjBlkLqTpGwSgYBaNgRAAAcBRArOhW1P8AAAAASUVORK5CYII=","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Xin","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2024-05-14 13:38:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4419605/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4419605/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57224080,"identity":"84fd8fb6-83f0-44a7-b0cf-e470f8ee0d86","added_by":"auto","created_at":"2024-05-27 16:39:05","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":959585,"visible":true,"origin":"","legend":"\u003cp\u003eAberrant expression levels and pathological stages of THOC3 in pan-cancer. (A) Expression analysis of THOC3 mRNA from tumor and normal tissues. (B) Combining TCGA and GTEx databases to obtain THOC3 mRNA expression levels. (C) THOC3 total protein levels between Lung adenocarcinoma ,Lung squamous cell carcinoma,ovarian cancer, Colon cancer,Glioblastoma multiforme,Clear cell RCC,Hepatocellular cancer and normal tissues were shown by CPTAC.(D) Association of THOC3 and pathological stages in SKCM, KIRP, TGCT, and COAD.( *p\u0026lt;0.05, **p\u0026lt;0.01 , ***p\u0026lt;0.001 and ****\u0026lt;0.0001)\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4419605/v1/107467d683d54a07212f6715.jpg"},{"id":57224250,"identity":"f2dc070c-d5cf-40a0-87b9-146625192914","added_by":"auto","created_at":"2024-05-27 16:47:05","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":605417,"visible":true,"origin":"","legend":"\u003cp\u003eThe survival plots and Kaplan-Meier curves with positive outcomes were given. (A) Correlation between THOC3 expression and OS of BRCA, CESC, LIHC, KIRC, LGG ,LUAD and PAAD. (B) Correlation between THOC3 expression and DFS of KICH, KIRP,PAAD and SKCM. patients.\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4419605/v1/9760053a6664f565252a6d3d.jpg"},{"id":57224083,"identity":"45521e9c-cf1d-41da-a726-99979faa3f69","added_by":"auto","created_at":"2024-05-27 16:39:05","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":229229,"visible":true,"origin":"","legend":"\u003cp\u003eGenetic alterations of THOC3 in pan-cancer using the cBioPortal.\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4419605/v1/f9ea9bba065f74deb68cd633.jpg"},{"id":57224091,"identity":"03e39877-a730-4fbc-b500-939a3bee0db3","added_by":"auto","created_at":"2024-05-27 16:39:06","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1153613,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation between THOC3 with two classes of immune checkpoint pathway genes[Inhibitory(24)、Stimulatory(36)].\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4419605/v1/1c20d14ee8083e271187db90.jpg"},{"id":57224088,"identity":"d768d003-9fb8-4f09-956b-82be49bb1218","added_by":"auto","created_at":"2024-05-27 16:39:06","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":158039,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier plots demonstrate differences in OS and PFS between THOC3 high and low expression groups after ICB treatment using SKCM cohorts.\u003c/p\u003e","description":"","filename":"Picture5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4419605/v1/8e87891caad98a3be8dff9e8.jpg"},{"id":57224092,"identity":"cef99209-d586-411f-82a6-994bfda018f7","added_by":"auto","created_at":"2024-05-27 16:39:06","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1008473,"visible":true,"origin":"","legend":"\u003cp\u003eThe correlation matrix between THOC3 expression and immune cell content. * p\u0026lt; 0.05.\u003c/p\u003e","description":"","filename":"Picture6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4419605/v1/7cf98b7ccefea7a54ed1ec7b.jpg"},{"id":57224252,"identity":"20c02c89-87db-4909-8593-08fdece2530d","added_by":"auto","created_at":"2024-05-27 16:47:05","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":1601110,"visible":true,"origin":"","legend":"\u003cp\u003eScatter plot of of the correlation by one algorithm in BRCA,BLCA,COADREAD,COAD,DLBC,ESCA,GBMLGG,HNSC,KICH,KIPAN,KIRC,KIRP,LGG,\u003c/p\u003e\n\u003cp\u003eLIHC,LUAD,LUSC,OV,PAAD,PRAD,READ,SARC,SKCM,SKCM-M,STAD,STES,THCA,UVM\u003c/p\u003e","description":"","filename":"Picture7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4419605/v1/595d34ce0f8ceaeacabb96f4.jpg"},{"id":57224087,"identity":"ab8c4438-502e-4e04-bcbf-8850f832cf05","added_by":"auto","created_at":"2024-05-27 16:39:06","extension":"jpg","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":262835,"visible":true,"origin":"","legend":"\u003cp\u003eThe correlation of THOC3 expression with TMB (A), MSI (B), and HRD (C).\u003c/p\u003e","description":"","filename":"Picture8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4419605/v1/8e7941eea6dc7aa69251704a.jpg"},{"id":57224084,"identity":"1f77a385-5e52-4235-be55-6c189ef1cec4","added_by":"auto","created_at":"2024-05-27 16:39:05","extension":"jpg","order_by":9,"title":"Figure 9","display":"","copyAsset":false,"role":"figure","size":616634,"visible":true,"origin":"","legend":"\u003cp\u003eThe function of THOC3 in single-cell functional analysis from the CancerSEA database. (A) Functional status of THOC3 in different human cancers. (B) Correlation analysis between functional status and THOC3 in AML,HNSCC, BRCA, OV, UVM, LUAD and RB. (* p \u0026lt; 0.05, ** p \u0026lt; 0.01,*** p \u0026lt; 0.001).\u003c/p\u003e","description":"","filename":"Picture9.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4419605/v1/d98aeb9d805dc2ea895610f0.jpg"},{"id":57224089,"identity":"830cb431-b8c6-479a-824f-33266aca5e62","added_by":"auto","created_at":"2024-05-27 16:39:06","extension":"jpg","order_by":10,"title":"Figure 10","display":"","copyAsset":false,"role":"figure","size":571021,"visible":true,"origin":"","legend":"\u003cp\u003e(A) Twenty genes co-expressed with THOC3 in GeneMANIA. (B) GO enrichment analysis of THOC3 related genes. (C) KEGG enrichment analysis of THOC3-related genes.\u003c/p\u003e","description":"","filename":"Picture10.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4419605/v1/58a2d7fe66fa0abcb741311d.jpg"},{"id":57224090,"identity":"51c8c6b2-7cc1-459e-a1bc-a8c79e22eacc","added_by":"auto","created_at":"2024-05-27 16:39:06","extension":"jpg","order_by":11,"title":"Figure 11","display":"","copyAsset":false,"role":"figure","size":827779,"visible":true,"origin":"","legend":"\u003cp\u003eAnalysis of THOC3 response to drug sensitivity in CellMiner database.\u003c/p\u003e","description":"","filename":"Picture11.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4419605/v1/1ca55db446834e8025924e43.jpg"},{"id":57224086,"identity":"7e2b4997-1efd-4682-b476-f0160576607a","added_by":"auto","created_at":"2024-05-27 16:39:05","extension":"jpg","order_by":12,"title":"Figure 12","display":"","copyAsset":false,"role":"figure","size":218727,"visible":true,"origin":"","legend":"\u003cp\u003e(A) the differential expression of THOC3 between LUAD and normal. (B) The survival analysis of THOC3 in LUAD (C)The calibration plots illustrating of the 1-year, 3-year, and 5-year OS probabilities. (D).The GSEA results of THOC3 in LUAD (E)Optical density ratio of the energy bands of THOC3 protein to the GAPDH bands by WB assays (F)The histogram represents the quantification of THOC3 in LUAD and normal; GAPDH was used as an internal control for WB. (**, P \u0026lt; 0.01) (G) The expression of THOC3 protein was higher in pancreatic cancer\u003c/p\u003e","description":"","filename":"Picture12.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4419605/v1/ec10e1da5e88479de33624a0.jpg"},{"id":63344101,"identity":"db774d41-2fcb-4d15-a12c-9fc4d1316d99","added_by":"auto","created_at":"2024-08-27 07:08:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8702199,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4419605/v1/579d5855-99eb-4833-85bf-b6d9f2cc70a4.pdf"},{"id":57224577,"identity":"3b1c2c98-0a9c-437f-a846-3a597322e042","added_by":"auto","created_at":"2024-05-27 16:55:05","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":17023,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4419605/v1/fd790dbc31d503892ccbd08c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"A comprehensive bioinformatics analysis of THOC3 highlights its potential role in pan-cancer and clinical significance in lung adenocarcinoma","fulltext":[{"header":"1.0: Introduction","content":"\u003cp\u003eCancer, influenced by factors like geographical distribution, lifestyle habits, genetics, and economic status, remains a leading cause of premature death globally\u003csup\u003e[3]\u003c/sup\u003e. Research anticipates a noteworthy rise in the prevalence of cancer patients in the upcoming decades, predominantly in low- and middle-income nations\u003csup\u003e[1,\u003c/sup\u003e\u003csup\u003e2]\u003c/sup\u003e. In cancer progression, gene expression transcription plays a critical role, with normal transcription processes being initiated and sustained by master transcription factors \u003csup\u003e[5]\u003c/sup\u003e. These master transcription factors interact with DNA enhancer elements, recruiting co-activators and transcription machinery to regulate gene expression \u003csup\u003e[6]\u003c/sup\u003e. Therefore, investigating the fundamental mechanisms of tumors, identifying key transcription factors in cancer patients, and discovering new therapeutic targets are of particular urgency.\u003c/p\u003e\n\u003cp\u003eThe THO complex (THOC), primarily comprising six subunits (THOC1~3 and THOC5~7), functions via the TREX complex within cells. This complex is integral to transcription, mRNA processing, export, DNA damage prevention, embryonic development, and cell differentiation in specific adult tissues\u003csup\u003e[4\u003c/sup\u003e\u003csup\u003e,7,\u003c/sup\u003e\u003csup\u003e8]\u003c/sup\u003e. Research has demonstrated that dysregulation of the THO complex is intricately linked to cancer, particularly influencing cell cycle regulation, DNA repair, and replication processes that contribute to cancer cell invasiveness, treatment resistance, and adverse patient outcomes\u003csup\u003e[9\u003c/sup\u003e\u003csup\u003e-\u003c/sup\u003e\u003csup\u003e14]\u003c/sup\u003e. The overexpression of THOC1 and THOC2 is associated with abnormal proliferation rates and cell cycle regulation in various cancers\u003csup\u003e[15\u003c/sup\u003e\u003csup\u003e-\u003c/sup\u003e\u003csup\u003e18]\u003c/sup\u003e; THOC5 plays a critical role in RNA 3' end processing and cell differentiation and is also associated with the formation of certain leukemias and solid tumors\u003csup\u003e[19\u003c/sup\u003e\u003csup\u003e,20]\u003c/sup\u003e; Extensive research has substantiated that the involvement of THOC7 contributes to the advancement of cutaneous squamous cell carcinoma, emphasizing its role in disease progression \u003csup\u003e[21]\u003c/sup\u003e. Aberrant expression of the THO complex may lead to imbalance in intracellular information transmission, affecting normal cell growth and death processes. Recent research has progressively uncovered THOC3's role in cancer development , McCormack NM and colleagues demonstrated that silencing the THOC3 gene markedly increases SMN protein levels, which regulate RNA metabolism and are closely linked to cell migration, invasion, and adhesion \u003csup\u003e[22\u003c/sup\u003e\u003csup\u003e,23]\u003c/sup\u003e. Yu T and colleagues discovered that elevated THOC3 expression leads to an increase in PFKFB4 levels, which consequently enhances glycolysis and facilitates the progression and motility of LUSC cells\u003csup\u003e[24]\u003c/sup\u003e. Additionally, research has suggested that the association of THOC3 with RNA-binding proteins (RBPs) holds potential as a prognostic indicator for patients with glioblastoma\u003csup\u003e[25]\u003c/sup\u003e. Nevertheless, the precise expression pattern and regulatory mechanism of THOC3 in various types of cancer remain uncertain within the academic community. This emphasizes the significance of conducting further investigations on the involvement of the THOC family in cancer. Exploring the impact of THOC3 in pan-cancer is urgently needed to improve patient prognosis.\u003c/p\u003e\n\u003cp\u003eIn this investigation, we carried out a comprehensive assessment of the association between THOC3 expression, its prognostic value, DNA alterations, and its implications across various types of cancer. This was achieved by integrating data from various databases and employing diverse bioinformatics methodologies. Additional analysis was conducted to investigate the correlation between THOC3 expression and the immune microenvironment in tumor tissues. A significant positive correlation was observed between THOC3 expression and pro-tumorigenic cells, which could result in inferior outcomes for patients with high levels of THOC3. These findings indicate that targeting THOC3 might offer a promising strategy for cancer therapy in the future. \u0026nbsp;\u0026nbsp;\u003c/p\u003e"},{"header":"2.0 Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Analysis of THOC3 expression in various tumors.\u003c/h2\u003e \u003cp\u003eTIMER 2.0 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://timer.cistrome.org/\u003c/span\u003e\u003cspan address=\"http://timer.cistrome.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) is a resource primarily focused on analyzing gene expression differences in tumors\u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. It enables researchers to estimate tumor immune infiltration using gene expression data, providing valuable insights into the molecular alterations in the tumor microenvironment. Given the absence of normal tissue controls for some tumors in TIMER 2.0, we sourced corresponding transcriptome data from the UCSC Xena database. Sangerbox (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://SangerBox.com\u003c/span\u003e\u003cspan address=\"http://SangerBox.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) is a tool for analyzing gene expression differences in tumors, aiding cancer research\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. Additionally, Using the UALCAN database, we explored THOC3's expression levels, phosphorylation status, and promoter methylation in various cancers\u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. Finally, The Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://gepia2.cancer-pku.cn/\u003c/span\u003e\u003cspan address=\"http://gepia2.cancer-pku.cn/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) is a useful tool for analyzing the correlation between gene expression and clinical information, including tumor staging in various types of cancer\u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Prognostic Analysis of THOC3 in Pan-Cancer\u003c/h2\u003e \u003cp\u003eThe Gene Expression Profiling Interactive Analysis 2 (GEPIA2) database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://gepia2.cancer-pku.cn/\u003c/span\u003e\u003cspan address=\"http://gepia2.cancer-pku.cn/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) is a powerful tool for studying the correlation between THOC3 gene expression and cancer patient survival time. It provides insights into the prognostic significance of THOC3 across various types of cancer. We categorized individuals into groups of high and low expression based on the median expression level of the THOC3 gene. Next, we employed the Kaplan-Meier approach to generate overall survival (OS) and disease-free survival (DFS) curves for both high and low THOC3 expression groups in the context of 33 cancer types. Finally, to compare survival between the two groups, we utilized the log-rank test.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3THOC3 Variation Analysis\u003c/h2\u003e \u003cp\u003ecbioportal (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.cbioportal.org/\u003c/span\u003e\u003cspan address=\"https://www.cbioportal.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) is a tool for analyzing genomic alterations to understand molecular features of tumors\u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. This platform has functionalities for analyzing gene mutation frequencies, mutation types (including mutations, amplifications, and multiple mutations), as well as mutation sites. In our study, we utilized this database to conduct a variation analysis of THOC3.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Immunological Checkpoint Analysis of THOC3\u003c/h2\u003e \u003cp\u003eThe expression data of THOC3 gene and 60 selected immune checkpoint pathway genes were analyzed in various samples from the UCSC database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://xenabrowser.net/\u003c/span\u003e\u003cspan address=\"https://xenabrowser.net/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e)\u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. We filtered out samples with expression levels of 0 and all normal samples. We transformed expression values using log2(x\u0026thinsp;+\u0026thinsp;1), then calculated Pearson correlations between THOC3 and immune pathway marker genes. Additionally, Through the TIDE database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://tide.dfci.harvard.edu\u003c/span\u003e\u003cspan address=\"http://tide.dfci.harvard.edu\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), we further investigated the significant correlation between THOC3 and PD1 as well as CTLA4\u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Immunological Correlation Analysis\u003c/h2\u003e \u003cp\u003eWe standardized the TCGA pan-cancer dataset from UCSC and transformed gene expression values using log2(x\u0026thinsp;+\u0026thinsp;1)\u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e. Subsequently, we mapped tumor gene expression profiles to GeneSymbol and evaluated immune scores using the deconvo_xCell method from the R package IOBR, while also examining the relationship between THOC3 and Th2 cells.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Relationship between THOC3 and TMB, MSI, HRD\u003c/h2\u003e \u003cp\u003eUsing the SangerBox tool, we retrieved a pan-cancer dataset from the UCSC Xena database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://xenabrowser.net/\u003c/span\u003e\u003cspan address=\"https://xenabrowser.net/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) that had undergone uniform standardization. Within this dataset, we integrated TMB (tumor mutation burden) alongside gene expression data derived from the samples. To enhance the sensitivity of data analysis, we performed a logarithmic transformation on each gene expression value, specifically log2(x\u0026thinsp;+\u0026thinsp;1). Additionally, we excluded single cancer types with sample sizes less than 3 to guarantee the validity and dependability of statistical analysis.Finally, we calculated the Pearson correlation between THOC3 gene expression and tumor mutation burden (TMB), microsatellite instability (MSI), and homologous recombination deficiency (HRD) to explore the potential associations between these biomarkers and THOC3 expression.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7 THOC3 Single Cell Functional Analysis and Gene Function Enrichment Analysis\u003c/h2\u003e \u003cp\u003eCancerSEA(\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://biocc.hrbmu.edu.cn/CancerSEA/\u003c/span\u003e\u003cspan address=\"http://biocc.hrbmu.edu.cn/CancerSEA/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) is a platform for analyzing cancer cell functions at the single-cell level\u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e. It is instrumental in studying the single-cell functional roles of THOC3 in cancer. GeneMANIA (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://genemania.org/\u003c/span\u003e\u003cspan address=\"http://genemania.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) is a freely accessible database and analysis tool that predicts gene functional associations by integrating diverse data sources\u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. It is utilized to identify the top 20 genes most correlated with THOC3 expression. The DAVID database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://david.abcc.ncifcrf.gov/\u003c/span\u003e\u003cspan address=\"http://david.abcc.ncifcrf.gov/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) is a bioinformatics resource offering comprehensive functional annotation for large-scale gene or protein lists\u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e. It facilitates functional enrichment analysis, including Gene Ontology (GO) analysis for biological processes, cellular components(CC), and molecular functions(MF). Additionally, it conducts pathway analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome databases, aiding in exploring THOC3 functional enrichment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.8 Correlation Analysis of THOC3 Expression and Drug Sensitivity\u003c/h2\u003e \u003cp\u003eThe CellMiner database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://discover.nci.nih.gov/cellminer/home.do\u003c/span\u003e\u003cspan address=\"https://discover.nci.nih.gov/cellminer/home.do\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) is a resource for investigating relationships between gene expression, including THOC3, and drug sensitivity. It provides RNA-seq expression data, drug activity information, and facilitates the selection of clinically tested and FDA-approved drugs for analysis using R packages like 'limma,' 'impute,' 'ggpubr,' and 'ggplot2'.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e2.9 The critical role of EMC6 in LUAD\u003c/h2\u003e \u003cp\u003eWe downloaded LUAD data from the UCSC database, and finally obtained 515 tumor samples and 59 normal tissue samples. We conducted differential analysis, survival analysis, prognosis analysis, and GSEA analysis on them. We selected four groups of human lung adenocarcinoma and adjacent normal specimens from the thoracic surgery department of the Fourth Hospital of Hebei Medical University for Western blot analysis and semi-quantitative evaluation of IHC. Using GAPDH protein as an internal reference, the results verified the significantly high expression of THOC3 protein in LUAD.\u003c/p\u003e \u003c/div\u003e"},{"header":"3.0 Results","content":"\u003cp\u003e3.1 Analysis of THOC3 Expression Levels in Various Cancer Tissues\u003c/p\u003e\n\u003cp\u003eThis study meticulously analyzed THOC3 mRNA expression, revealing pronounced upregulation in 13 cancers: BLCA,BRCA, CESC,COAD,CHOL,ESCA,HNSC,LIHC,LUAD,LUSC,READ, STAD,UCEC. In contrast, it was downregulated in KICH(Fig. 1A). Due to the limited availability of normal samples in the TCGA database, we integrated data from both TCGA and GTEx databases. This allowed us to assess the variability in THOC3 expression across 34 cancer types, ensuring a comprehensive analysis(Fig. 1B). Moreover, the UALCAN database helped us determine THOC3 protein expression levels in LUAD、LUSC、OV、COAD、GBM、KIRC and LIHC, all of which showed high expression(Fig. 1C). Furthermore, we utilized the GEPIA2 database to investigate the correlation between THOC3 expression levels and disease staging, revealing significant associations in SKCM, KIRP, TGCT, and COAD (p \u0026lt; 0.05, Fig. 1D).\u003c/p\u003e\n\u003cp\u003e3.2Prognostic Value of THOC3 Across Cancers\u003c/p\u003e\n\u003cp\u003eThis study thoroughly assessed the impact of THOC3 expression levels on prognosis across 33 cancer types. In the overall survival (OS) analysis, high THOC3 expression was found to be significantly associated with shorter survival times in BRCA, LIHC, LGG, LUAD, and PAAD samples. Conversely, low THOC3 expression is associated with shorter survival times in KIRC and CESC (p \u0026lt; 0.05, Fig. 2A). In the disease-free survival (DFS) analysis, elevated THOC3 expression was pinpointed as a risk factor for shorter DFS in KICH, KIRP, PAAD, and SKCM (p \u0026lt; 0.05, Fig. 2B).\u003c/p\u003e\n\u003cp\u003e3.3 DNA Mutation Analysis\u003c/p\u003e\n\u003cp\u003eUtilizing the cBioPortal database, this study conducted a comprehensive analysis of THOC3 gene mutations across a spectrum of cancers. It was found that amplification is the primary mutation type for the THOC3 gene, occurring most frequently at 33.75% in pancreatic neuroendocrine tumors. Notably, papillary gastric adenocarcinoma and uterine serous carcinomas exhibited significant amplification rates of 10% each, while renal clear cell carcinoma displayed a rate of 9.01% (Fig. 3). Furthermore, oral squamous cell carcinoma and head and neck squamous cell carcinoma primarily exhibited deep deletions, with frequencies of 7.69% and 2.33%, respectively.\u003c/p\u003e\n\u003cp\u003e3.4 Analysis of THOC3 Expression in Multiple Cancers and Its Relationship with Immune Checkpoint (ICP) Genes.\u003c/p\u003e\n\u003cp\u003eIn a variety of cancer types, THOC3 expression consistently correlates positively with immune checkpoint (ICP) genes, observed in cancers including LAML, KICH, KIPAN, KIRC, OV, and PAAD; in contrast, a negative correlation is evident in LUSC and THCA. More than 90% of cases involving the ICP genes CD276, VEGFA, and HMGB1 show a correlation with THOC3 expression (Fig. 4). These observations imply that elevated THOC3 expression could predict the effectiveness of immune therapies targeting ICP genes. Additionally, analysis using the TIDE database examined the link between ICB therapy responses and THOC3 expression levels. According to a 2017 PD1 cohort study by Riaz, high THOC3 expression correlates with reduced overall survival (OS) in melanoma (SKCM) patients; a 2019 study by Gide on PD1+CTLA4 indicated that elevated THOC3 expression is linked to decreased progression-free survival (PFS) in melanoma cases (Fig. 5).\u003c/p\u003e\n\u003cp\u003e3.5 Analysis of THOC3\u0026apos;s Association with Immune Cell Profiles and Th2 Cells in Various Cancers\u003c/p\u003e\n\u003cp\u003eBased on the findings depicted in Figure 6, a positive correlation is evident between THOC3 expression and pro-oncogenic immune cells, including Th2 cells, common lymphoid progenitors (CLP), megakaryocytic-erythroid progenitors (MEP), osteoblasts, and vascular smooth muscle cells (VSMC). Conversely, THOC3 expression shows a negative correlation with immune cells known for their anti-tumor activity, such as CD8+ T cells, monocytes, macrophages, and Th1 cells. Th2 cells, a type of auxiliary T cell, play a significant role in the progression and severity of tumors. This study employed the CIBERSORT technique to examine the correlation between THOC3 and Th2 cells across a broad spectrum of cancers. Research indicates that heightened THOC3 expression correlates with augmented infiltration of Th2 cells in certain cancers, including BRCA, BLCA, COADREAD, COAD, DLBC, ESCA, GBMLGG, HNSC, KICH, KIPAN, KIRC, KIRP, LGG, LIHC, LUAD, LUSC, PAAD, PRAD, READ, SARC, SKCM, SKCM-M, STAD, STES, THCA, and UVM. On the other hand, in ovarian cancer (OV) and thyroid carcinoma (THCA), high THOC3 expression significantly reduces Th2 cell infiltration (p \u0026lt; 0.05, Figure 7).\u003c/p\u003e\n\u003cp\u003e3.6 Exploring the Interactions Between THOC3 and Genetic Markers of Cancer Susceptibility: TMB, MSI, and HRD\u003c/p\u003e\n\u003cp\u003eThis study delved into the correlations between THOC3 expression and key genetic markers in oncology, namely TMB, MSI and HRD, across diverse tumor types. Notably, THOC3 demonstrated a noteworthy positive correlation with TMB in various cancers, including GBM, GBMLGG, LUAD, STES, STAD, PRAD, MESO, READ, and PCPG, but exhibited a negative correlation in LUSC (Figure 8A). Furthermore, THOC3 expression displayed a positive correlation with MSI in STES, SARC, and STAD, while exhibiting a negative correlation in GBMLGG, KIPAN, and PRAD (Figure 8B). Moreover, an analysis of HRD was conducted to further explore how THOC3 expression influences resistance to platinum-based chemotherapy treatments. The findings revealed that THOC3 significantly positively correlates with HRD in a range of cancers, including GBM, LUAD, BRCA, ESCA, STES, SARC, KIRP, KIPAN, PRAD, HNSC, KIRC, LUSC, LIHC, OV, and KICH (Figure 8C).\u003c/p\u003e\n\u003cp\u003e3.7 Single-cell functional enrichment analysis of the THOC3\u003c/p\u003e\n\u003cp\u003eIn this investigation, we conducted single-cell functional enrichment analysis of the THOC3 gene across various cancer types, including AML, LUAD, OV, RCC, BRCA, HNSCC, RB, and UM (Figure 9A). Our examination, facilitated by the CancerSEA database, revealed significant associations between THOC3 expression and diverse cellular functions within each cancer context. Specifically, in AML, THOC3 expression exhibited a positive correlation with gene silencing and metastasis. Within HNSCC, THOC3 expression correlated positively with cell stemness and gene silencing, while showing a negative correlation with angiogenesis. Conversely, in BRCA, THOC3 expression was positively linked with DNA repair functionality. Notably, in OV, THOC3 expression displayed a negative correlation with tumor cell invasion. Similarly, in UM, THOC3 displayed negative associations with cell apoptosis, DNA damage, and DNA repair processes. In LUAD, THOC3 expression exhibited positive correlations with the cell cycle, DNA damage, and DNA repair, while showing negative correlations with inflammatory processes. Finally, in RB, THOC3 expression exhibited positive correlations with angiogenesis, cell differentiation, and inflammatory processes, while displaying negative correlations with DNA repair, cell cycle, and DNA damage processes (Figure 9B).\u003c/p\u003e\n\u003cp\u003e3.8 Functional Enrichment Analysis of THOC3\u003c/p\u003e\n\u003cp\u003eWe utilized the GeneMANIA database to extract the top 20 genes that exhibited the strongest correlation with THOC3 (Figure 10A). Following, we performed an in-depth analysis of the potential biological functions and pathways linked to THOC3 and these 20 interacting genes utilizing the DAVID database. The enrichment analysis for biological processes (BP) demonstrated that THOC3-related genes were predominantly involved in RNA splicing, mRNA processing, mRNA nuclear export, and the export of viral mRNA from the host cell nucleus (Figure 10B). The enrichment analysis for molecular functions (MF) indicated that THOC3 was involved in protein binding, RNA binding, and mRNA binding (Figure 10C). In the enrichment analysis for cellular components (CC), THOC3-related genes were found to be enriched in the nucleoplasm, cytoplasm, and nucleolus (Figure 10D). Additionally, KEGG pathway analysis revealed the involvement of THOC3 in nucleocytoplasmic transport and spliceosome pathways (Figure 10E).\u003c/p\u003e\n\u003cp\u003e3.9 Drug Sensitivity Analysis\u003c/p\u003e\n\u003cp\u003eEmploying the CellMiner database, we investigated the Pearson correlation between THOC3 expression levels and drug sensitivity. The results indicate a positive correlation between the sensitivity of Allopurinol, Cladribine, Fludarabine, Bisacodyl (the active ingredient of Viraplex), Amuvatinib, Cpd-401, Econazole Nitrate, ARTENIMOL, artesunate, and the expression level of THOC3. Conversely, the sensitivity of WORTMANNIN, Depsipeptide, RAF-265, Cediranib, and Pluripotin is negatively correlated with the expression level of THOC3 (Figure 11). These results indicate a noteworthy negative correlation between THOC3 expression and the sensitivity to Pluripotin and RAF-265.\u003c/p\u003e\n\u003cp\u003e3.10 Differential Analysis and Immunological Analysis of THOC3 in Lung Adenocarcinoma\u003c/p\u003e\n\u003cp\u003eTo investigate the role of THOC3 further, we conducted a comparative analysis of THOC3 protein expression between tumor tissues and normal tissues. The results illustrated in Figure 12A demonstrate a notably elevated expression of THOC3 in tumor tissues relative to normal tissues, with significant disparities observed particularly in LUAD tissues. Through univariate COX regression analysis, we established that THOC3 significantly impacts the prognosis of LUAD patients and can function as an independent prognostic indicator for LUAD (Figure 12B). Furthermore, the correlation between THOC3 expression and 1-year, 3-year, and 5-year overall survival rates (OS) was examined using ROC curves, yielding area under the curve (AUC) values of 0.70, 0.71, and 0.73, respectively. These results reinforce the crucial role of elevated THOC3 expression in predicting unfavorable prognosis among LUAD patients (Figure 12C).. Our gene set enrichment analysis (GSEA) revealed that THOC3 significantly influences tumor transcription imbalance, chemokine signaling pathways, and axon guidance, as depicted in Figure 12D. These findings suggest the potential involvement of THOC3 in the pathogenesis of lung adenocarcinoma. To validate the disparities in THOC3 expression between tumor tissues and normal tissues, we analyzed four sets of human lung adenocarcinoma and adjacent normal specimens obtained from the Department of Thoracic Surgery, Fourth Affiliated Hospital of Hebei Medical University. Immunoblot analysis and semi-quantitative immunohistochemical scoring confirmed the substantial overexpression of THOC3 in lung adenocarcinoma (Figure 12E, F, G). The observed overexpression of THOC3 in tumors strengthens its potential as a novel target for treating LUAD.\u003c/p\u003e"},{"header":"4.0 Discussion","content":"\u003cp\u003eIn recent years, with the advancement of personalized medicine, notably the swift evolution of targeted therapy and immunotherapy, substantial strides have been achieved in cancer treatment, enhancing the outcomes for individuals facing advanced or metastatic cancer\u003csup\u003e[37]\u003c/sup\u003e. However, overall clinical outcomes remain unsatisfactory. The challenge of treating advanced cancer has prompted researchers to explore the underlying mechanisms driving cancer growth, aiding in the identification of effective therapeutic targets. Transcription refers to the process of genetic information flowing from DNA to RNA, with the cell's transcription program established and maintained by master transcription factors\u003csup\u003e[5]\u003c/sup\u003e. Cancer development is closely associated with transcriptional regulation within cells, and aberrant transcription factors are considered potential breakthroughs in cancer therapy\u003csup\u003e[38]\u003c/sup\u003e. The THOC3 gene, located on chromosome 5, encodes a protein that is a highly conserved part of the TREX complex. THOC3 plays a crucial regulatory role in splicing and recruitment during transcription, and it is also an important factor in regulating RNA-binding proteins (RBPs), as confirmed by existing research\u003csup\u003e[22\u003c/sup\u003e\u003csup\u003e,39,\u003c/sup\u003e\u003csup\u003e40]\u003c/sup\u003e. Currently, research on THOC3 in cancer is limited to a few specific types of cancer, such as lung squamous cell carcinoma and glioma, with no studies yet addressing THOC3 in various cancer types. In our study, we found that THOC3 is also involved in processes such as DNA damage repair, cell death, angiogenesis, and tumor immune infiltration. Therefore, THOC3 may serve as a promising biomarker.\u003c/p\u003e\n\u003cp\u003eIn this investigation, we meticulously analyzed the data from the TCGA dataset to assess THOC3 expression across diverse tissue types. Our findings revealed a significant upregulation of THOC3 expression across multiple cancer types, with the exception of TGCT and KICH. Recognizing the potential discrepancies between protein and mRNA expression levels due to post-transcriptional modifications, we further scrutinized THOC3 protein expression in diverse cancer types. Our analysis unveiled a notable increase in THOC3 protein levels in cancers such as LUAD, LUSC, OV, COAD, GBM, and LIHC. Additionally, empirical evidence corroborated significant overexpression of THOC3 in LUAD. Our results underscore the significant association between THOC3 expression and cancer staging in SKCM, KIRP, TGCT, and COAD, encompassing clinical stages. Furthermore, both overall survival (OS) and disease-free survival (DFS) analyses exhibited a pronounced correlation between THOC3 expression and cancer patient prognosis. Specifically, high THOC3 levels were associated with shorter overall survival in BRCA, LGG, LIHC, LUAD, and PAAD, while showing a positive correlation with longer survival in CESC and KIRC. In terms of DFS, elevated THOC3 expression correlated with reduced disease-free survival in KICH, KIRP, PAAD, and SKCM. These results emphasize the critical importance of THOC3 in prognostic evaluations, establishing it as a dependable prognostic indicator for cancer.\u003c/p\u003e\n\u003cp\u003eMutations in genes and aberrant DNA methylation are recognized as critical factors that disrupt gene expression in cancers, markedly influencing both the onset and progression of the disease. Such genetic alterations predominantly affect key cellular processes including proliferation, apoptosis, and repair mechanisms\u003csup\u003e[41,\u003c/sup\u003e\u003csup\u003e42]\u003c/sup\u003e. Typically, genetic changes associated with cancer manifest as point mutations, deletions, or chromosomal rearrangements. Nevertheless, in various cancer types, the THOC3 gene primarily exhibits its oncogenic potential through gene amplification\u003csup\u003e[43]\u003c/sup\u003e.This occurrence involves a notable rise in the gene's copy numbers, resulting in the excessive production of its protein. Consequently, this heightened production significantly enhances the growth and viability of cancerous cells\u003csup\u003e[44]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eImmunotherapy has demonstrated remarkable effectiveness in various solid tumors, representing a significant breakthrough in cancer treatment. However, the clinical remission rates are still relatively modest, underscoring the urgency for more refined and targeted immunotherapeutic strategies\u003csup\u003e[45]\u003c/sup\u003e. The tumor microenvironment (TME) constitutes a critical nexus for tumor proliferation and the invasion by immune and stromal cells. In our comprehensive study examining THOC3 expression across 39 cancer types, we observed a strong association between THOC3 expression and cell subgroups that support tumor development, such as Th2 cells, common lymphoid progenitors, myeloid-erythroid progenitors, osteoprogenitors, and vascular smooth muscle cells. Conversely, THOC3 expression is significantly inversely correlated with cytotoxic cells such as CD8+ T cells, monocytes, macrophages, and Th1 cells, which are involved in suppressing tumor progression. Notably, Th2 cells, often linked with promoting tumor progression, also contribute to angiogenesis and suppress the cellular mechanisms responsible for tumor cell elimination. Thus, THOC3 may play a crucial role in enabling tumor cells to evade immune surveillance and destruction, potentially enhancing tumor-associated angiogenesis\u003csup\u003e[46,\u003c/sup\u003e\u003csup\u003e47]\u003c/sup\u003e. Furthermore, our findings demonstrate a significant positive correlation between THOC3 and key immune checkpoint genes, namely CD276, VEGFA, VEGFB, CD274, and HMGB1. These correlations offer novel perspectives on the role of THOC3 in the manipulation of immune checkpoint pathways pathways, paving the way for the development of innovative immune checkpoint inhibitors.\u003c/p\u003e\n\u003cp\u003eTumor mutational burden (TMB) and microsatellite instability (MSI) have been firmly established as robust biomarkers for the prognosis of various cancers and as indicators of the efficacy of several tumor immunotherapies\u003csup\u003e[28]\u003c/sup\u003e. High levels of TMB and MSI in tumors have been associated with a more favorable response to immunotherapy\u003csup\u003e[48\u003c/sup\u003e\u003csup\u003e,50]\u003c/sup\u003e. Through our analysis, we found a robust positive correlation between THOC3 and TMB in various tumor types, particularly in cases of LUSC. Moreover, in STES and STAD, THOC3 expression is significantly associated with both TMB and MSI, implying that high THOC3 expression could confer enhanced survival benefits post-immunotherapy in these contexts. Additionally, homologous recombination deficiency (HRD) is closely linked with increased sensitivity to platinum-based chemotherapy and PARP inhibitors, with THOC3 showing significant correlations with HRD across 15 tumor types\u003csup\u003e[49]\u003c/sup\u003e. This observation suggests that STES patients, who exhibit substantial correlations with TMB, MSI, and HRD, might achieve superior outcomes with a therapeutic regimen combining immunotherapy and PARP inhibitors. Consequently, THOC3 emerges as a promising new target for anticancer immunotherapy strategies.\u003c/p\u003e\n\u003cp\u003eUtilizing the CancerSEA platform, we conducted an exhaustive pan-cancer functional evaluation of THOC3. Our single-cell functional investigations unveiled a significant positive relationship between THOC3 and DNA damage as well as metabolic processes, while demonstrating a distinct inverse association with DNA repair mechanisms in certain cancer types. These findings emphasize THOC3's critical role in regulating gene expression stability and modulating cellular stress responses in cancer cells. Emerging research has indicated that suppression of THOC3 expression in LUSC significantly reduces levels of cell cycle-associated proteins and curtails tumor cell migration\u003csup\u003e[24]\u003c/sup\u003e. Functional enrichment analysis underscores THOC3's primary engagement in cell cycle regulation, DNA transcription, and protein stability across diverse cancers, consistent with previous research\u003csup\u003e[51]\u003c/sup\u003e. Furthermore, drug sensitivity testing has demonstrated that agents such as Pluripotin and RAF-265 effectively suppress THOC3 expression. These insights not only affirm THOC3's fundamental role in the survival and motility of cancer cells but also accentuate its potential as a promising therapeutic target. Continued investigations into THOC3 as an emerging drug target are paving new paths for cancer therapy.\u003c/p\u003e\n\u003cp\u003eWhile the impact of THOC3 in pan-cancer has been described, it is important to note some limitations. Firstly, all analyses are based on bioinformatics, and THOC3 expression has only been confirmed in lung adenocarcinoma through Western blot (WB) and immunohistochemistry (IHC). Secondly, our study did not investigate the molecular mechanism of THOC3 in cancer. Therefore, it is essential to conduct further research to explore the expression mechanism of THOC3 in tumors in future studies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eBased on this study and related online data, THOC3 is identified as playing a pivotal, multifunctional role in tumor progression. It regulates critical pathways like gene expression stability, cell cycle, and DNA transcription, impacting tumor cell survival and migration. THOC3\u0026apos;s involvement with immune regulation and tumor microenvironment also provides new directions for cancer therapy. Understanding THOC3\u0026apos;s molecular mechanisms in cancer is crucial, as it helps enhance its potential as a therapeutic target and prognostic biomarker, thereby improving cancer treatment strategies. Nonetheless, further research is essential to fully elucidate THOC3\u0026apos;s action mechanisms and its potential clinical applications.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAUTHOR CONTRIBUTIONS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJixin Zhang performed bioinformatics analysis and completed the manuscript. All authors gave final approval to the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGMENTS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets for this study can be found in the public databases TCGA, GTEx, DAVID,CellMiner, GEPIA2,CancerSEA,Sangerbox and cBioportal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This research received no external funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u003c/strong\u003e The original manuscript contained in the research report is included in the article/Supplementary Materials. Further inquiries can be made directly to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest:\u0026nbsp;\u003c/strong\u003eThe authors declare no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSoerjomataram I, Bray F. 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PMID: 36674977; PMCID: PMC9865438.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","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":"THOC3, pan-cancer, prognosis, immune cell infiltration, Drug Sensitivity","lastPublishedDoi":"10.21203/rs.3.rs-4419605/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4419605/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTHOC3, a crucial component of the THO complex, is involved in mRNA biosynthesis and export. Studies have shown that dysregulation of THOC3 is linked to various aspects of tumorigenesis, including tumor initiation, progression, and metastasis. In this study, we utilized a comprehensive bioinformatics analysis to explore the role of THOC3 in different types of cancer. Our analysis of different types of data helped us understand how THOC3 contributes to cancer at the molecular level, and its clinical significance. Moreover, our immune analysis revealed notable correlations between THOC3 and multiple immune-related signaling pathways. Our findings highlight the potential oncogenic role of THOC3 across different types of cancer and propose dysregulation of THOC3 as a key driver in tumor development. Furthermore, the associations between THOC3 and immune-related signaling pathways indicate its potential as a target for further experimental validation and investigation in the realm of immunotherapy.\u003c/p\u003e","manuscriptTitle":"A comprehensive bioinformatics analysis of THOC3 highlights its potential role in pan-cancer and clinical significance in lung adenocarcinoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-27 16:39:00","doi":"10.21203/rs.3.rs-4419605/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":"1c1ddc5a-3ce0-4d69-96f4-86030dd93a9a","owner":[],"postedDate":"May 27th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-27T06:59:53+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-27 16:39:00","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4419605","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4419605","identity":"rs-4419605","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}