The role of hypoxia-inducible factor-1α on colon cancer progression and metastasis

The role of hypoxia-inducible factor-1α on colon cancer progression and metastasis | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL This is a preprint and has not been peer reviewed. Data may be preliminary. 30 January 2025 V1 Latest version Share on The role of hypoxia-inducible factor-1α on colon cancer progression and metastasis Authors : 8888 , Rafid Albadr , Gaurav Sanghvi , R. Roopashree , Aditya Kashyap , A. Sabarivani , Jasur Rizaev , Waam Taher , Mariem Alwan , Mahmood Jawad , and Ali Al-Nuaimi Authors Info & Affiliations https://doi.org/10.22541/au.173822610.08360262/v1 356 views 97 downloads Contents Abstract Supplementary Material Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Despite the advancements in technological innovations and scientific research in the field of clinical oncology, colon cancer remains one of the predominant factors of cancer-related death all around the world. Hypoxic conditions, characterized by diminished oxygen levels in the tumor microenvironment, are implicated in the tumorigenesis of various types of cancer. HIF-1α, as a principal hypoxic transcription factor, promotes tumor progression due to its interaction with multiple molecular pathways and oncogenic function. Various researches have demonstrated that HIF-1α can increasingly promote the growth and development of colon tumor cells by stimulating downstream target genes through multiple mechanisms such as immune evasion, cancer stem cell enrichment, metastasis, invasion, angiogenesis, and glycolysis. In this review, we will comprehensively review the mechanisms and functions of HIF-1α that contribute to the growth and progression of colon cancer in the hypoxic tumor microenvironment. 1. Introduction Colon cancer is classified among the most prevalent malignancies globally, with 500,000 and 140,000 new diagnoses occurring annually in Europe and the United States, respectively. This malignancy is correlated with an estimated 250,000 and 70,000 deaths in these regions 1 . Similar to other forms of cancer, metastases constitute the principal cause of mortality among colon cancer patients, with the liver being a common site for these distant metastases. Notably, around 25% of patients exhibit such metastases at the point of diagnosis 2 . Among the various types of metastases, metachronous metastases exhibit the highest mortality rates, impacting 20-25% of affected patients. The survival rate (five-year) for individuals diagnosed with colon cancer accompanied by distant metastases is about 12%, while this rate increases to 90% for patients with localized colon cancer 3 . A variety of risk factors, including dietary habits, physical activity, and genetic susceptibility, are linked to the prevention and aggression of colon cancer, highlighting the need for comprehensive research and heightened public awareness 4 . Various cellular components in the tumor microenvironment (TME), like endothelial cells, cytokines, growth factors, and cancer cells have been identified to inhibit the function of tumor-infiltrating leukocytes and enhance immune response inhibitory signals, thereby facilitating cancer progression 5 . Tumor cells utilize multiple strategies and mechanisms to evade antitumor immune responses. Numerous studies have indicated that hypoxia and its related factors, resulting from insufficient oxygen levels in the TME, are linked to the growth and proliferation of tumor cells and are recognized as effective escape mechanisms 6 . Hypoxia inhibits immune responses and induces drug resistance by downregulating the transcription of hundreds of genes related to metastasis, invasion, angiogenesis, and tumorigenesis 7 . Hypoxia-inducible factor-1 (HIF-1), known as the principal transcription factor induced under hypoxia conditions, plays a special function in carcinogenesis, upregulation of cancer cell survival, and tumor-promoting processes 8 . The two main subunits of HIF-1, HIF-1α, and HIF-1β, are induced in response to acute hypoxic stimuli. HIF-1α can be stabilized through both hypoxia-independent and -dependent pathways, and its role has been demonstrated in various cancers, particularly colon cancer 9 . HIF-1α plays a significant function in promoting the colony formation and survival of colon cancerous cells within the TME by enhancing cell migration, diminishing apoptosis, increasing angiogenesis, boosting nutrient altering, and modifying glycolysis 10-12 . Numerous studies and investigations are still being conducted to clarifying the function of HIF-1α in colon cancer progression. Researchers believe that due to the crucial significance of HIF-1α in the progression of various types of cancer, especially colon cancer, further investigation are required to find the different mechanisms associated with HIF-1α as well as targeting them, which may provide effective antitumor strategies for colon cancer treatment. In this study, we will examine a variety of research findings and discuss the impact of HIF-1α on colon cancer progression and metastasis. 2. HIF-1α and tumorigenesis Tumorigenesis is a complicated multistep interaction that is linked to the development of the TME, induction of tumor-promoting factors, as well as the interaction between several metabolic pathways 13 . The rapid growth and spread of tumor cells, along with inefficient blood supply, create hypoxic conditions in the center of the TME. To adapt to these low-oxygen conditions, tumor cells activate the most important regulators of oxygen homeostasis, namely the hypoxia-inducible factors (HIF-1) 14 . Among these, HIF1-α and HIF1-β are the most important HIF-1 factors, with the β subunit being constitutively expressed, while the α subunit’s expression is dependent on oxygen levels 15 . In response to hypoxic conditions, tumor cells promote cancer progression by increasing the induction of the HIF1-α transcription factor through various mechanisms such as cancer stem cell (CSC) maintenance, drug resistance, epithelial-mesenchymal transition (EMT), metastasis, cell migration, angiogenesis, and extracellular matrix remodeling 16, 17 . Tumor cells stimulate angiogenesis within the TME by upregulating the overexpression of vascular endothelial growth factor (VEGF). Various researches have demonstrated that upon the emergence of hypoxia in the TME, HIF1-α markedly elevates the expression levels of VEGF. Additionally, HIF1-α also facilitates the migration of endothelial cells into hypoxic areas to overcome oxygen deficiency and produce new blood vessels 18, 19 . To maintain ATP production in the hypoxic TME, anaerobic metabolic pathways play a more important role than oxidative phosphorylation 10 . HIF1-α typically regulates glucose metabolism in hypoxic tumors because cancer cells express various HIF1-α -moderated genes associated with glucose metabolism to compensate for oxygen deprivation 20 . Furthermore, HIF1-α is involved in several metabolic processes, including such as induction of enzymes responsible for pyruvate clearance, facilitation of glucose to pyruvate conversion, and activation of glucose transporters such as GLUT1 and GLUT3 21, 22 . HIF-α also prevents the recruitment of immune cells into the TME. Several examinations have illustrated that HIF-1α enhances the function of immune-inhibitory cells such as myeloid-derived suppressor cells (MDSCs) as well as tumor-associated macrophages (TAM) in the TME 23, 24 . These cells are partly activated by the upregulation of the cytokine VEGF and chemokines like CCL12 and CXCL5 25 . HIF1-α promotes suppressive functions and enhances the recruitment of tumor-associated macrophages and MDSCs by amplifying hypoxia-related signaling 26 . After the recruitment of these cells, VEGF is released by tumor-associated macrophages in the hypoxic tumor area, which promotes tumor cell colony formation, metastasis, and angiogenesis 27 . HIF-1α enhances the expression of adenosine receptors on tumor-infiltrating immune cells and increases adenosine levels in the tumor area, thereby contributing to the suppressive effects of tumor hypoxia on immune cells. Signaling of the A2A receptor (A2AR) inhibits cytokine production and proliferation of T cells 28, 29 . Furthermore, HIF-1α elevates the expression of immunosuppressive molecules like CTLA-4 on CD8+ T lymphocytes and PD-L1 on cancer cells, thereby neutralizing T cell-mediated antitumor responses 30 . HIF-1α also rises the overexpression of the FoxP3 gene in T lymphocytes, that enhances the activation and frequency of regulatory T lymphocytes (Tregs) within hypoxic tumors. Tumor cells release Treg-specific attractant cytokines and chemokines, such as CCL28 and TGF-β to recruit CXCR10-, neuropilin-1-, and CCR10-expressing Tregs to the TME 31, 32 . In addition to hypoxic conditions, tumor cells utilize various oxygen-independent pathways to stabilize and promote HIF-1α expression and its downstream signaling pathways. For instance, HIF-1α can be upregulated in an oxygen-independent manner by mutation of tumor suppressor genes or constitutive expression of oncogene genes 33 . Von Hippel-Lindau protein (vHL), a tumor inhibitor regulated by HIF-1α, moderates HIF-1α expression through ubiquitination and proteasomal degradation under normal conditions. The vHL recognizes hydroxylated prolines within a complex comprising elongin C and B and then, together with DD8, acts as an E3 ubiquitin ligase to facilitate the targeting and degradation of HIF-1α 34 . In contrast, the vHL ubiquitin ligase complex cannot target HIF-1α under hypoxic conditions and instead, it is moved to the nucleus. Studies have shown that dysfunction and absence of vHL expression in renal cancer significantly elevate the levels of HIF-1α and HIF-2α, ultimately resulting in carcinogenesis 35 . Therefore, it can be concluded that HIF expression by cancer stem cells can be considered important due to their potential to moderate the expression of more than 100 of tumor-associated genes and promote tumorigenesis under both normoxic and hypoxic conditions. 3. Colon cancer and therapeutic strategies Cancer represents one of the most widespread health issues affecting individuals and stands as the second leading cause of mortality worldwide, following heart disease 36 . Colon cancer has emerged as a critical concern and a significant challenge in global health today, accounting for approximately 10% of all cancer cases 37 . Annually, colon cancer is responsible for about 60,000 fatalities, with around 6% of the global population being impacted by this disease 38 . While genetic factors contribute minimally to the etiology of colon cancer—accounting for roughly 8% of cases—the incidence of this cancer is markedly increased in individuals with a familial predisposition 39, 40 . Colon cancer has the potential to metastasize to other regions of the body if not identified and treated promptly. Research indicates that approximately 20% of patients present with metastases at the time of diagnosis, underscoring the critical need for the identification and implementation of effective treatment strategies for this malignancy 41 . Metastasis serves as a significant prognostic indicator for recurrent colon cancer and can rapidly impact vital organs, including the lungs, liver, and stomach; however, the precise molecular mechanisms underlying this process remain unknown 41, 42 . Polyposis syndromes like familial adenomatous polyposis (FAP) and non-polyposis such as hereditary non-polyposis colorectal cancer (HNPCC) are classified in the category of hereditary and genetic susceptibility to colon cancer 43, 44 . It is estimated that approximately 2% of newly diagnosed cases of colon cancer are attributable to polyposis syndromes, which are associated with the loss or mutation of FAP, the most prevalent genetic alteration linked to colon cancer. These mutations facilitate the tumorigenesis of colon cancer cells and contribute to the early onset of colon adenoma progression 45 . In contrast, about 80% of colon cancers are linked to HNPCC syndrome, which arises from mutations in DNA mismatch repair genes 46 . In the tumor microenvironment of colon cancer, two isoforms, CCAT1 and CCAT2, have been identified as transcription factors associated with colon cancer 47 . CCAT1 exhibits a significant potential to enhance C-MYC expression and upregulate microRNAs, functioning as an enhancer-patterned RNA 48 . Conversely, CCAT2 facilitates cancer progression and tumorigenesis through inducing the Wnt/β-catenin axis and downregulating energy metabolism 49 . Research demonstrated that the overactivation of the Wnt gene or an increase in mutations within the β-catenin gene can lead to the induction of PPAR-δ, c-Myc, and cyclin D1 expression, promoting progression of colon adenomas 50 . The assessment of symptoms associated with colon conditions, such as weight loss, diarrhea, abdominal pain, rectal, and bleeding alterations in bowel habits can facilitate the early identification of colon cancer; however, it is noteworthy that many individuals may not exhibit these symptoms 51 . A prevalent classification system for colon cancer is the TNM classification, which categorizes the disease based on tumor size, lymph node involvement, and metastasis, with grades ranging from I to IV 52, 53 . The pathological stage of the cancer is closely linked to its prognosis, with each grade reflecting distinct prognostic implications The most effective and common technique for diagnosing colon cancer is endoscopy, specifically through procedures such as colonoscopy and sigmoidoscopy 54 . These methods enable histological examination of the intestinal tissue and facilitate the identification of tumor locations and intestinal polyps 55 . Furthermore, colonoscopy has proven to be a valuable tool in diagnosing patients with colon neoplasia 56 . Imaging tests demonstrate enhanced efficacy in the identification and detection of colon cancer. Notable techniques include abdominal ultrasonography, PET/CT scan, roentgenographic thoracic examination (RTG), nuclear magnetic resonance (NMR) and endorectal ultrasonography (USG). These methods are particularly significant in the assessment of severe focal lesions 57 . Nowadays, common treatment modalities for colon cancer encompass a range of approaches, including combination therapies, targeted therapy, surgical intervention, radiotherapy, chemotherapy, and immunotherapy 58 . The management of colon cancer is usually based on the attempt to remove the bowel and adjacent lymph nodes. For patients diagnosed with Grade I colon cancer, a colectomy may suffice as a treatment option. In contrast, Grade III and IV colon cancer necessitate more extensive interventions, including curative bowel resection, surgical procedures, and a combination of various therapeutic modalities. Furthermore, in cases where patients exhibit a poor prognosis, palliative care may be prioritized over chemotherapy. Evidence suggests that combination therapies are usually more effective than single treatments due to fewer side effects, lower toxicity, and additive or synergistic action 59 . Therefore, more research and studies are needed not only to find new techniques for the prevention, treatment, and diagnosis of colon cancer but also to identify the underlying mechanisms associated with colon tumor cell migration, chromosomal instability, and genetic mutations 60 . 4. HIF-1α in colon carcinogenesis This section will explore the role of HIF-1α in proliferation, survival, angiogenesis, migration, invasion, and its potential to be a therapeutic agent in colon cancer (Table 1 and Figure 1). 4.1. Proliferation and survival Hypoxic conditions have been demonstrated to promote both the protein and mRNA levels of S-glutathionylation of HIF-1α in colon tumor cells, an effect that is significantly reduced by the depletion of glutathione and the reduction of oxidized glutathione. Additionally, hypoxic tumor cells that exhibit overexpression of glutaredoxin-1 demonstrate resistance to the induction of hypoxia-responsive genes and HIF-1α. Consequently, the S-glutathionylation of HIF-1α may facilitate the colony formation and proliferation of cancerous cells through the activation of HIF-1α, positioning it as a prospective therapeutic factor for the advancement of innovative pharmacological compounds 61 . Also, research indicates that HIF-1α is markedly overactivated in individuals diagnosed with colon cancer. Zheng et al. have suggested a possible relationship between the overexpression of HIF-1α and CDX2 within colorectal adenocarcinoma. Their findings revealed that approximately 63% and 70% of patients exhibited overexpression of HIF-1α and CDX2 level, respectively. Adding CoCl2 to create hypoxic conditions in SW480 and LS174T cells, it was observed that HIF-1α downregulated CDX2 expression in colon TME while promoting cellular proliferation of cancerous cells 62 . Conversely, it has been reported that cytokine-induced killer (CIK) cells can enhance immune reconstitution and improve the hypoxic tumor microenvironment in 26 colon cancer xenograft mice. The HIF-1α levels, the percentage of CD8+ T cells, and tumor volume were progressively diminished in the CIK-treated groups in comparison to the untreated groups, while the level of CD4+ T cells increased. Thus, CIK cells exhibit a significant potential to suppress the growth, proliferation, as well as survival of colon cancerous cells 63 . In addition, disrupting HIF-1α function significantly reduced non-hypoxia-induced cell survival and proliferation both in vivo and in vitro. While HIF-1α is recognized as a critical factor for cell survival and proliferation in hypoxic conditions, its impact on hypoxic compartments within tumor xenografts in vivo appears to be limited, particularly in RKO and HCT116 cell lines 64 . Furthermore, the Protein/nucleic acid deglycase DJ-1, that is overexpressed in colon cancerous tissues, has been identified as a regulator of HIF-1α level via the PI3K/AKT axis. Both in vivo and in vitro experiments have illustrated a positive interaction between DJ-1 and HIF-1α, indicating that DJ-1 facilitates the progression and survival of colon tumor cells under hypoxic conditions through the PI3K/AKT/HIF-1α pathway 65 . Additionally, research conducted by Long and colleagues has highlighted the significant role of arginine ADP-ribosyltransferase 1 (ART1) in the growth, proliferation, and overall mass of tumor cells in tumor-bearing BALB/c mice, which is mediated by the upregulation of HIF-1α, GLUT1, LDH, and p-AKT gene expression. In addition, ART1 regulates GLUT1-dependent glycolysis in CT26 cells through the PI3K/AKT/HIF-1α pathway, thereby enhancing glucose utilization in the TME 66 . 4.2. Angiogenesis, invasion and metastasis Research has demonstrated that HIF-1α, CD133, and ANXA3 expression levels are dramatically elevated in patients diagnosed with colon cancer. In vivo results have shown that there is a direct correlation between HIF-1α, CD133, and ANXA3, and their high expression in the tumor microenvironment is closely related to the clinical parameters, including stage, angiogenesis, metastasis, invasion, and tumor size of colon cancer. These factors may function as potential molecules for the colon cancer treatment and diagnosis 67 . Mu et al. reported a positive correlation between semaphorin4D (Sema4D) and HIF-1α, noting that their expression levels were markedly increased within the tumor microenvironment of colon cancer. Their findings revealed that tumor cells and tumor-associated macrophages (TAMs) exhibiting elevated expression levels of HIF-1α and Sema4D facilitated endothelial tube formation and enhanced angiogenesis, invasion, and metastasis of colon cancer cells. These cells were also associated with TNM stages, specific histological types, and lymphatic metastasis 68 . Surprisingly, data indicated that the RNA helicase YTHDC2 significantly upregulated the translation of HIF-1α both in vitro and in vivo, thereby promoting the invasion, angiogenesis, and metastasis of colon tumor cells. Therefore, YTHDC2 may serve as a target gene and a diagnostic biomarker in the management and diagnosis of colon cancer patients 69 . Additionally, lncRNA IGFL2-AS1 has been shown to promote the invasion, migration, and angiogenesis of colon tumor cells in vivo and in vitro by suppressing HIF‐1α degradation and increasing the expression of carbonic anhydrase 9 (CA9) 70 . 4.3. Prognosis and treatment Tumor cells have been demonstrated to rise the accumulation of HIF-1α, VEGF, as well as IL-8 in HT29 cells through the upregulation of the A3 adenosine receptor, Akt, p38, and ERK1/2 genes. The data showed that treatment of tumor cells with caffeine and adenosine analog could disrupt the adenosine-dependent HIF-1α/VEGF/IL-8 signaling cascade, suppressing the survival and proliferation of colon cancerous cells 71 . In a separate investigation, Kikuchi et al. reported that the aberrant expression of mutant BRAF and KRAS genes activates HIF-1α expression in Caco2 cells. Their findings demonstrated that the knockdown of BRAF and KRAS using the MEK inhibitor PD98059 and the PI3k inhibitor LY294002 increasingly diminished HIF-1α protein synthesis and prevented the progression of HCT116 and DLD-1 tumor cells 72 . Furthermore, the inhibition of the 26S proteasome and Aldose reductase using fidarstat and MG132 was found to suppress the induction of MMP2, lysyl oxidase, VEGF, GSK3β, and the PI3K/AKT pathway, as well as to inhibit both mRNA and protein level of HIF-1α in Caco-2, HT29, and SW480 cells. The authors suggested that targeting Aldose reductase could influence HIF-1α expression and potentially inhibit tumor invasion and progression 73 . Additionally, Iovine and colleagues discovered that L-carnosine, by disrupting the ubiquitin-proteasome system, diminished the transcriptional activity and protein levels of HIF-1α in the HCT-116 cell line, leading to a reduction in HIF-1α-mediated cellular proliferation. This therapeutic strategy may prove to be effective and ideal in the treatment of various cancer types like colon cancer and hypoxia-associated malignancies 74 . In a subsequent study, Kim et al. reported that treatment of HCT116 cells with sulforaphane isolated from broccoli significantly reduced the VEGF and HIF-1α levels and inhibited metastasis, colony formation, angiogenesis, and progression of colon cancer. These data demonstrated that sulforaphane could act as a promising treatment agent for colon cancer 75 . Furthermore, HIF-1α has been shown to enhance aerobic glycolysis in colon cancer cells through the regulation of enolase 2 (ENO2) expression. Pan et al. reported that the treatment of LoVo and HCT116 cancer cells with naringin, extracted from grapefruit , effectively suppressed the of HIF-1α level, leading to a reduction in the migration, proliferation, and glycolytic activity of colon tumor cells 76 . Additionally, the application of ursolic acid has been illustrated to diminish the tumor cells sensitivity to chemotherapeutic agents like oxaliplatin and 5-fluorouracil (5-FU). Ursolic acid was capable of inhibiting the accumulation of HIF-1α, which in turn diminished the VEGF level and multidrug resistance protein 1 (MDR1) in hypoxic colon cancer cell lines, including SW480, RKO, and LoVo, thereby preventing the invasion and angiogenesis of cancer cells 77 . Moreover, administration of verbascoside could prevent metastasis, angiogenesis, and invasion of tumor cells in the HT29 cell line by suppressing the signaling pathways associated with HIF-1α, Rac-1, and Zeb-1. Also, other genes associated with cancer progression such as VEGF, Pak1, and Arp2 were significantly reduced, confirming the anti-invasive and anti-metastatic activities of verbascoside 78 . Kim and colleagues showed that HIF1-α significantly increased the expression of endothelial cell-specific molecule-1 (ESM-1) in individuals diagnosed with colon cancer. The inhibition of HIF-1α could cause a markedly reduction in ESM-1 level, indicating its potential as a therapeutic biomarker for colon cancer treatment 79 . Moreover, HIF-1α plays a crucial function in moderating the transcription of cancer-specific variants of organic anion transporting polypeptide 1B3 (OATP1B3) in various colon cancer cell lines, for example in HCT8, HCT-116, DLD-1, SW480, and Caco-2 cells. The investigations demonstrated that blocking HIF-1α via HIF-1α siRNA could significantly inhibit the promoter HRE of csOATP1B3, thereby diminishing the expression and proliferation of colon tumor cells 80 . Lv et al. reported an increase in multidrug resistance-associated protein 1 (MRP1) and HIF-1α within the colon cancer TME following the administration of cobalt chloride. Their findings indicated a positive correlation between HIF-1α and MRP1, with the use of HIF-1α siRNA leading to a reduction in MRP1 expression. Results from luciferase assays confirmed that HIF-1α specifically attach to the HRE region in the MRP1 promoter, thereby promoting its expression and contributing to multidrug resistance in colon cancer treatment 81 . In another study, Sun and colleagues assessed the impact of hypoxia on radiosensitivity and autophagy in SW620 and SW480 colon cell lines. Their data revealed a direct correlation between microRNA-210 (miR-210) and HIF-1α. The suppression of HIF-1α through HIF-1α siRNA led to diminished expression of autophagy-related factors and miR-210, while inhibition of miR-210 was associated with increased survival of colon cancer cells post-radiotherapy and elevated levels of Bcl-2. These findings suggest that the HIF-1α/miR-210/Bcl-2 axis plays an important function in the induction of autophagy and the reduction of radiosensitivity in a hypoxic TME 82 . It has also been reported that there is a positive correlation between the RhoA/ROCK2 pathway and the HIF-1α gene. Specifically, the silencing of HIF-1α level through siRNA could cause a simultaneous reduction in the gene’s expression level linked to the RhoA/ROCK2 axis, like MMP2, cyclin D1, and pMYPT1. Furthermore, the administration of Y-27632, an inhibitor of the RhoA/ROCK2 pathway, led to a reduction in the colony formation, growth, proliferation, and invasion of cancerous cells under hypoxic TME. This suggests that HIF-1α indicates a regulatory function in the RhoA/ROCK2 axis, thereby contributing to the metastasis and progression of colon cancer 83 . Additionally, a study conducted by Langhammer et al. demonstrated that the inhibition of the lactate dehydrogenase (LDH-A) gene increased HIF-1α expression; however, it did not influence the expression of its downstream regulated proteins, including prolyl hydroxylase 2 (PHD2), factor-inhibiting HIF (FIH), VEGF, and carbonic anhydrase IX (CAIX) in vivo. The results proposed that while LDH-A is critical for the proliferation and progression of HT29 cell lines, the utilization of LDH-M (muscle) could indicate an ideal therapeutic method for the treatment of colon cancer 84 . Pencreach and colleagues demonstrated that the combination therapy of rapamycin and irinotecan, in contrast to monotherapy, significantly inhibits the mammalian rapamycin/HIF-1α axis and markedly reduces tumor volume in xenograft models. In vitro experiments revealed that this combination therapy induces substantial cell death in HCT-116 and HT-29 cell lines under hypoxic conditions. Consequently, the synergistic use of low-dose rapamycin and irinotecan presents a promising therapeutic strategy for targeting HIF-1α in the treatment of colon cancer 85 . In a separate investigation, Zhang et al. found that inhibiting HIF-1α expression using shRNA silencing HIF-1α could cause a diminish in the level of hypoxia-induced target genes, including P-glycoprotein, glucose transporter 1, and VEGF. They also reported that by inhibiting HIF-1α expression, the intensity and duration of the antitumor effect of metronomic combination therapy with low-dose paclitaxel in HT-29 xenograft tumor model could be significantly enhanced, thereby demonstrating potent antitumor activity against colon cancer 86 . Additionally, parthenolide was shown to dramatically inhibit the HIF-1α expression and hypoxia-associated proteins, including EMT, angiogenesis, and glucose metabolism by suppressing NF-κB expression. This suggests that PT not only modulates EMT, NF-κB, and HIF-1α specific markers in tissue samples but also has the potential to inhibit metastasis and cancer progression in colorectal cancer xenograft models 87 . Mi and colleagues reported that digitoxin, a cardiovascular drug, in addition to reducing HIF-1α expression by inhibiting 4E-BP1 and p70S6K phosphorylation, can also inhibit the expression of p-STAT3 and STAT3 proteins in KRAS-mutated SW620 and SW480 cells. Digitoxin exhibits a strong potential to suppress tumor cell migration and proliferation and significantly increases the induction of apoptosis by blocking STAT3 and HIF-1α, thereby suppressing tumor growth in a mouse xenograft transplantation model. This drug may represent a suitable alternative for treating patients with cetuximab-resistant human colon cancer 88 . In addition, Wogonin derived from Scutellaria Baicalensis Georgi has demonstrated antitumor activity in HCT116 cells and murine tumor models. Data indicated that wogonin not only inhibits the expression of proteins associated with glycolysis and lactate production, such as LDHA, PDHK1, and HKII but also downregulates HIF-1α expression by suppressing the PI3K/Akt signaling pathway. In addition, wogonin effectively suppressed the growth of transplantable tumors, suggesting its potential as a promising strategy for enhancing the reversal of multidrug resistance (MDR) 89 . Xu and colleagues identified that hypoxic cells through the HIF-1α/miR-338-5p/IL-6 axis induce drug resistance in colon cancer patients. Their findings revealed a reduction in miR-338-5p level in HCT8 and HCT116 cell lines and a reverse relationship between miR-338-5p and both IL-6 and HIF-1α in CRC patient samples. Furthermore, in vivo experiments demonstrated that the blockage of HIF-1α using the PX-478 inhibitor, along with the miR-338-5p overactivation in a xenograft model, enhanced the sensitivity of colon tumor cells to oxaliplatin through inhibiting HIF-1α/miR-338-5p/IL-6 axis 90 . Additionally, Dey et al. reported a positive correlation between HIF-1α and MDR, which contributes to the advancement of drug resistance within the TME of colon cancer. In vitro and in vivo experiments indicated that treatment with the CopA3 peptide led to the activation of p53 and the proteasomal degradation of HIF-1α, significantly diminishing hypoxia-induced angiogenesis and drug resistance 91 . Role of HIF-1α In vivo/in vitro Cell line/ Animal model Drug Major outcome Ref Proliferation and survival In vitro RKO, DLD-1, and HCT 116 - S-glutathionylation of HIF-1α induced the growth and proliferation of cancer cells by activation of HIF-1α 61 In vitro SW480 and LS174T - HIF-1α reduced the CDX2 level and promoted colon cancerous cell growth 62 In vivo Male Kunming mice - CIK cells enhanced immune reconstitution and improve the hypoxic tumor microenvironment 63 In vivo and in vitro Female athymic nu/nu mice HCT116 and RKO - HIF-1α induced non-hypoxia-Mediated Proliferation of colon cancer cells 64 In vivo and in vitro Female athymic BALB/c nude mice SW480 and HT-29 - DJ-1 promoted the progression and survival of colon tumor cells through the PI3K/AKT/HIF-1α axis 65 In vivo and in vitro Female athymic BALB/c mice CT26 - ART1 regulated GLUT1-dependent glycolysis through the PI3K/AKT/HIF-1α axis 66 Angiogenesis, invasion and metastasis In vivo Human colorectal carcinoma samples - HIF-1α, CD133 and ANXA3 levels increased significantly in patients with colon cancer 67 In vivo and in vitro LoVo, HUVECs and THP-1 Human colorectal carcinoma tissue specimens - TAMs with increased expression of HIF-1α and Sema4D enhanced colon cancer cell angiogenesis and metastasis 68 In vivo and in vitro Female BALB/c nu/nu mice HT29, HCT116 and COS - HIF-1α translation significantly increased by the RNA helicase YTHDC2 69 In vivo and in vitro Male BALB/c‐nu nude mice SW480, SW620, Caco2, HT29, LoVo, NCM460, and the 293T - IGFL2-AS1 by inhibiting of HIF‐1α degradation and increasing the CA9 level enhanced the invasion, migration and angiogenesis of colon tumor cells 70 Prognosis and treatment In vitro HT29 Caffeine, adenoassociated virus (AAV) and Cre recombinase Caffeine and adenosine analog disrupted the adenosine-dependent HIF-1α/VEGF/IL-8 axis 71 In vitro HKe-3, HK2-10, DKO-3, DKs-5, Caco2, HT29, HCT116, and DLD-1 Proteasome inhibitor MG132, MEK inhibitor PD98059, and PI3K inhibitor LY294002 Aberrant expression of mutant BRAF and KRAS activated HIF-1α expression level 72 In vitro HT29, SW480, and Caco-2 Fidarestat and 26 S proteasome inhibitor MG132 Inhibition of Aldose reductase affected the HIF-1α, preventing tumor invasion and progression 73 In vitro HCT116 L-carnosine L-carnosine reduced transcriptional activity and protein levels of HIF-1α 74 In vitro HCT116 Sulforaphane Sulforaphane reduced the VEGF and HIF-1α expression and inhibited metastasis and progression of colon cancer 75 In vitro LoVo and HCT116 Naringin Naringin blocked HIF-1α, thereby inhibited the migration, proliferation, and glycolysis of colon tumor cells 76 In vitro RKO, LoVo, and SW480 Ursolic acid Ursolic acid inhibited the HIF-1α accumulation and reduced the VEGF and MDR1 levels in hypoxic cells 77 In vitro HT29 Verbascoside Verbascoside prevented metastasis, angiogenesis, and invasion of cancerous cells by suppressing HIF-1α, Rac-1, and Zeb-1 78 In vitro HT29 HIF-1α siRNA HIF1-α significantly increased the expression of ESM-1 in colon cancer cells 79 In vitro HCT116, DLD-1, HCT-8, SW480, and Caco-2 HIF-1α siRNA HIF-1α played an important function in regulating the transcription of OATP1B3 in colon cancer cells 80 In vitro Lovo HIF-1α siRNA HIF-1α specifically attached to the HRE region in the MRP1 promoter and induced its expression level 81 In vitro SW480 and SW620 miR-210 siRNA and HIF-1α siRNA HIF-1α/miR-210/Bcl-2 axis played an important role in the induction of autophagy and the reduction of radiosensitivity in hypoxic tumor environment 82 In vitro SW480, SW620, HCT116, and HT29 Y-27632 and HIF-1α siRNA There is a positive correlation between the RhoA/ROCK2 axis and the HIF-1α gene 83 In vivo Male athymic nude mice shRNA silencing HIF-1α Inhibition of LDH-A gene increased HIF1α expression in colon cancer cells 84 In vivo and in vitro Male athymic nude mice HCT-116, HT-29, SW480, and Caco2 Irinotecan and rapamycin Combination therapy of rapamycin and irinotecan significantly inhibited the rapamycin/ HIF-1α axis and tumor volume 85 In vivo and in vitro Male BALB/c nude mice HT-29 shRNA silencing HIF-1α and paclitaxel By inhibiting HIF-1α expression, the intensity and duration of antitumor effect of metronomic combination therapy with low-dose paclitaxel in HT-29 xenograft tumor model 86 In vivo and in vitro Female athymic nude mice HT-29, DLD-1 and HCT116 Parthenolide PT regulated EMT, NF-κB, and HIF-1α and suppressed metastasis and progression of colon cancer 87 In vivo and in vitro Male BALB/c nude mice SW480 and SW620 cells Digitoxin Digitoxin suppressed migration and proliferation of cance cells and increased the induction of apoptosis by blocking STAT3 and HIF-1α 88 In vivo and in vitro Male BALB/c nude mice HCT116 Wogonin Wogonin inhibited the expression of HIF-1α through inhibition of the PI3K/Akt axis 89 In vivo and in vitro Male athymic nude mice HCT116 and HCT8 OXA, 5-FU, DOX, CTX, PX-478 and miR-338-5p inhibitors Hypoxic cells induced drug resistance in TME by the HIF-1α/miR-338-5p/IL-6 axis 90 In vivo and in vitro Male BALB/c nude mice HCT-116 CopA3 CopA3 induced proteasomal degradation of HIF-1α and activation of p53 91 5. Conclusion and future perspectives Due to the high rate of proliferation and competition for food and energy between normal and cancerous cells in the TME, the oxygen level decreases to a high degree, which is called hypoxia 92 . One of the most important factors that is induced under hypoxic conditions is HIF-1α, which has attracted significant interest from researchers in recent decades regarding its role in the tumorigenesis of various cancers, particularly colon cancer 93 . Since various factors are associated in the development of colon cancer and are controlled by a complex network, targeting HIF-1α indicates a promising agent for therapeutic intervention. Numerous investigations have proposed various therapeutic approaches aimed at targeting HIF-1α, including: 1) inhibiting HIF-1 dimerization, 2) inhibiting HIF-1α protein synthesis, 3) facilitating the degradation of the HIF-1α protein, 4) diminishing HIF-1α mRNA levels, and 5) inhibiting HIF-1α-related proteins 94 . While targeting HIF-1α presents new therapeutic possibilities for colon cancer patients, these strategies encounter several challenges and require confirmation and evaluation of complementary studies such as treatment regimens, patient tolerability, and clinical efficacy in real-world settings. Also, the activation of HIF-1α involves a complex mechanism influenced by various factors. Although effective therapeutic strategies for colon cancer have been developed, further investigation is needed to optimize drug delivery systems and identify suitable drug carriers. The inhibition and blockade of HIF-1α have been demonstrated as an effective therapeutic strategy for the treatment of colon cancer. Combining current therapeutic approaches with new techniques aimed at blocking HIF-1α could be effective and efficient, which requires evaluating the mechanism of action and including them in clinical trials. Furthermore, novel nanoparticle-based drug delivery systems can be employed to improve the detection and targeting of HIF-1α within the tumor microenvironment. The application of drug or anti-HIF-1α siRNA-loaded nanoparticles has demonstrated efficacy in suppressing HIF-1α expression, thereby preventing the progression, invasion, angiogenesis, and colony formation of colon tumor cells 95-97 . Drug delivery systems have unique features for targeted cancer therapy, including preventing cancer cell resistance to chemotherapeutic drugs, fewer side effects, and simultaneous targeting of multiple pathways 98 . Ultimately, future research will elucidate the regulatory mechanisms of the HIF-1α pathway in the tumorigenesis and modulation of colon cancer stem cell functionality during normal cellular development, to design effective therapeutic methods for the treatment of colon cancer. Figure legend Figure 1: The role of HIF-1α in colon cancer progression. Under normoxic conditions (sufficient oxygen), HIF-1α is hydroxylated by prolyl hydroxylase domain (PHD) enzymes, leading to its recognition by the von Hippel-Lindau (VHL) tumor suppressor protein and subsequent proteasomal degradation. However, in hypoxic environments, such as those found within solid tumors, HIF-1α is stabilized and translocates to the nucleus. There, it dimerizes with HIF-1β and binds to hypoxia response elements (HREs) in the promoter regions of target genes, thereby upregulating their expression. These target genes play crucial roles in promoting colon cancer hallmarks, including angiogenesis, metabolic reprogramming, invasion and metastasis, and resistance to apoptosis and immune surveillance. Abbreviation Tumor microenvironment (TME); Hypoxia-inducible factor-1 (HIF-1); Cancer stem cell (CSC); Epithelial-mesenchymal transition (EMT); Vascular endothelial growth factor (VEGF); Myeloid-derived suppressor cells (MDSCs); Tumor-associated macrophages (TAM); A2A receptor (A2AR); Regulatory T lymphocytes (Tregs); Familial adenomatous polyposis (FAP); Hereditary non-polyposis colorectal cancer (HNPCC); Toentgenographic thoracic examination (RTG); Nuclear magnetic resonance (NMR); Endorectal ultrasonography (USG); Cytokine-induced killer (CIK); ADP-ribosyltransferase 1 (ART1); Semaphorin4D (Sema4D); Tumor-associated macrophages (TAMs); Carbonic anhydrase 9 (CA9); Enolase 2 (ENO2); 5-fluorouracil (5-FU); Multidrug resistance protein 1 (MDR1); Endothelial cell-specific molecule-1 (ESM-1); Organic anion transporting polypeptide 1B3 (OATP1B3); MicroRNA-210 (miR-210); Lactate dehydrogenase (LDH-A); Prolyl hydroxylase 2 (PHD2); Factor-inhibiting HIF (FIH); Carbonic anhydrase IX (CAIX); LDH-M (lactate dehydrogenase-muscle); Von Hippel-Lindau (VHL); Hypoxia response elements (HREs) Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of interest There is nothing to declare. Acknowledgments Not applicable. Consent for publication All of the authors consent for this article publication CRediT authorship contribution statement Mohamed J. Saadh: Writing – original draft, Methodology, Data curation. Mareb Hamed Ahmed: Conceptualization, Writing – review & editing, Supervision. Rafid Jihad Albadr: Writing – review & editing. Gaurav Sanghvi: Writing – review & editing. R. Roopashree: Writing – review & editing. Aditya Kashyap: Writing – review & editing. A. Sabarivani: Writing – review & editing. Jasur Rizaev: Writing – review & editing. Waam Mohammed Taher: Writing – review & editing. Mariem Alwan: Writing – review & editing. Mahmood Jasem Jawad: Data curation. Ali M. Ali Al-Nuaimi: Data curation. Availability of data and materials The data generated in the present study may be requested from the corresponding author. Ethics approval and consent to participate Not applicable. 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Roopashree JAIN (Deemed-to-be University) View all articles by this author Aditya Kashyap Chitkara University View all articles by this author A. Sabarivani Sathyabama University View all articles by this author Jasur Rizaev Samarkand State Medical Institute View all articles by this author Waam Taher Directorate General of Education in Dhi Qar View all articles by this author Mariem Alwan Al-Farahidi University View all articles by this author Mahmood Jawad Al-Zahrawi University College View all articles by this author Ali Al-Nuaimi Gilgamesh Ahliya University View all articles by this author Metrics & Citations Metrics Article Usage 356 views 97 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation 8888, Rafid Albadr, Gaurav Sanghvi, et al. The role of hypoxia-inducible factor-1α on colon cancer progression and metastasis. Authorea . 30 January 2025. 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