COMPREHENSIVE ANALYSIS OF COL1A1 EXPRESSION, METHYLATION, AND GENETIC ALTERATIONS IN LIVER HEPATOCELLULAR CARCINOMA
Main Article Content
Keywords
LIHC, COL1A1, Diagnosis, Treatment
Abstract
Liver hepatocellular carcinoma (LIHC) is a prevalent and deadly form of liver cancer characterized by significant genetic and epigenetic alterations. This study focuses on the role of COL1A1, a gene implicated in various cancers, by analyzing its expression, promoter methylation, and genetic mutations in LIHC. Using the UALCAN database, we observed a significant upregulation of COL1A1 in LIHC samples compared to normal controls, suggesting its involvement in cancer progression. This finding was corroborated by GEPIA2 analysis, which also showed elevated COL1A1 expression in LIHC. Further analysis using UALCAN revealed that COL1A1 expression was consistently upregulated across different cancer stages, races, ages, and genders of LIHC patients, indicating its broad role in tumor development. Validation with GEPIA2 confirmed these observations at individual cancer stages. Methylation analysis showed that COL1A1 was hypomethylated in LIHC samples relative to normal controls, a factor known to enhance tumor development. Interestingly, stage-specific analysis indicated hypermethylation of COL1A1 in stage 4 LIHC, reflecting its complex regulatory mechanisms. Survival analysis using KM plotter and GEPIA2 indicated that higher COL1A1 expression was associated with lower overall survival (OS) rates in LIHC patients, although the results were not statistically significant. Genetic alteration analysis via cBioPortal identified a low mutation frequency (3%) in COL1A1, suggesting limited impact on LIHC through genetic mutations alone. In conclusion, our comprehensive analysis highlights COL1A1 as a potentially significant player in LIHC progression through its aberrant expression and methylation, although its direct genetic mutations appear to have minimal effect. These findings underscore the need for further research to fully elucidate COL1A1's role and therapeutic potential in LIHC.
References
2. Bray F, Laversanne M, Weiderpass E, Soerjomataram I. The ever‐increasing importance of cancer as a leading cause of premature death worldwide. Cancer. 2021;127(16):3029-30.
3. Usman M, Hameed Y, Ahmad M. Does human papillomavirus cause human colorectal cancer? Applying Bradford Hill criteria postulates. ecancermedicalscience. 2020;14.
4. Yabroff KR, Wu X-C, Negoita S, Stevens J, Coyle L, Zhao J, et al. Association of the COVID-19 pandemic with patterns of statewide cancer services. JNCI: Journal of the National Cancer Institute. 2022;114(6):907-9.
5. Khan M, Hameed Y. Discovery of novel six genes-based cervical cancer-associated biomarkers that are capable to break the heterogeneity barrier and applicable at the global level. Journal of Cancer Research and Therapeutics. 2023.
6. Ahmad M, Khan M, Asif R, Sial N, Abid U, Shamim T, et al. Expression characteristics and significant diagnostic and prognostic values of ANLN in human cancers. International Journal of General Medicine. 2022:1957-72.
7. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians. 2018;68(6):394-424.
8. Xu W, Li H, Hameed Y, Abdel-Maksoud MA, Almutairi SM, Mubarak A, et al. Elucidating the clinical and immunological value of m6A regulator-mediated methylation modification patterns in adrenocortical carcinoma. Oncology Research. 2023;31(5):819.
9. Hameed A, Condò C, Tauseef I, Idrees M, Ghazanfar S, Farid A, et al. Isolation and Characterization of a Cholesterol-Lowering Bacteria from Bubalus bubalis Raw Milk. Fermentation. 8 (4): 163. 2022.
10. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2024;74(3):229-63.
11. Barata PC, Rini BI. Treatment of renal cell carcinoma: Current status and future directions. CA Cancer J Clin. 2017;67(6):507-24.
12. Zhou H, Gul Y, Hameed Y, Alhomrani M, Alghamdi SA, Almalki AA, et al. Unveiling the unexplored novel signatures for osteoporosis via a detailed bioinformatics and molecular experiments based approach. American Journal of Translational Research. 2024;16(4):1306.
13. Usman M, Hameed Y, Ahmad M. Does epstein–barr virus participate in the development of breast cancer? A brief and critical review with molecular evidences. Biomedical and Biotechnology Research Journal (BBRJ). 2020;4(4):285-92.
14. Identification of Key Biomarkers for the Future Applications in Diagnostics and Targeted Therapy of Colorectal Cancer. Current Molecular Medicine. 2022.
15. Dong Y, Wu X, Xu C, Hameed Y, Abdel-Maksoud MA, Almanaa TN, et al. Prognostic model development and molecular subtypes identification in bladder urothelial cancer by oxidative stress signatures. Aging. 2024;16(3):2591-616.
16. Kaur H, Bhalla S, Raghava GPS. Classification of early and late stage liver hepatocellular carcinoma patients from their genomics and epigenomics profiles. PLoS One. 2019;14(9):e0221476.
17. El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142(6):1264-73. e1.
18. Hameed Y. Decoding the significant diagnostic and prognostic importance of maternal embryonic leucine zipper kinase in human cancers through deep integrative analyses. Journal of Cancer Research and Therapeutics. 2023;19(7):1852-64.
19. Sun S, Wang Y, Wu Y, Gao Y, Li Q, Abdulrahman AA, et al. Identification of COL1A1 as an invasion‑related gene in malignant astrocytoma. International journal of oncology. 2018;53(6):2542-54.
20. Lin Z, Zeng J, Wang X. Compound phenotype of osteogenesis imperfecta and Ehlers–Danlos syndrome caused by combined mutations in COL1A1 and COL5A1. Bioscience Reports. 2019;39(7):BSR20181409.
21. Maasalu K, Nikopensius T, Kõks S, Nõukas M, Kals M, Prans E, et al. Whole-exome sequencing identifies de novo mutation in the COL1A1 gene to underlie the severe osteogenesis imperfecta. Human genomics. 2015;9:1-5.
22. Karamat U, Ejaz S, Hameed Y. In silico-analysis of the multi-omics data identified the ataxia telangiectasia mutated gene as a potential biomarker of breast invasive carcinoma. Genetic Testing and Molecular Biomarkers. 2021;25(4):263-75.
23. Wiechec E, Magan M, Matic N, Ansell-Schultz A, Kankainen M, Monni O, et al. Cancer-associated fibroblasts modulate transcriptional signatures involved in proliferation, differentiation and metastasis in head and neck squamous cell carcinoma. Cancers. 2021;13(13):3361.
24. Ucaryilmaz Metin C, Ozcan G. Comprehensive bioinformatic analysis reveals a cancer-associated fibroblast gene signature as a poor prognostic factor and potential therapeutic target in gastric cancer. BMC cancer. 2022;22(1):692.
25. Zhang T, Li X, He Y, Wang Y, Shen J, Wang S, et al. Cancer-associated fibroblasts-derived HAPLN1 promotes tumour invasion through extracellular matrix remodeling in gastric cancer. Gastric Cancer. 2022:1-14.
26. Poplawski P, Rybicka B, Boguslawska J, Rodzik K, Visser TJ, Nauman A, et al. Induction of type 1 iodothyronine deiodinase expression inhibits proliferation and migration of renal cancer cells. Molecular and Cellular Endocrinology. 2017;442:58-67.
27. Brooks M, Mo Q, Krasnow R, Ho PL, Lee Y-C, Xiao J, et al. Positive association of collagen type I with non-muscle invasive bladder cancer progression. Oncotarget. 2016;7(50):82609.
28. Hu H, Umair M, Khan SA, Sani AI, Iqbal S, Khalid F, et al. CDCA8, a mitosis-related gene, as a prospective pan-cancer biomarker: implications for survival prognosis and oncogenic immunology. American Journal of Translational Research. 2024;16(2):432.
29. Zhang Z, Wang Y, Zhang J, Zhong J, Yang R. COL1A1 promotes metastasis in colorectal cancer by regulating the WNT/PCP pathway. Mol Med Rep. 2018 2018/04/01;17(4):5037-42.
30. Hou L, Lin T, Wang Y, Liu B, Wang M. Collagen type 1 alpha 1 chain is a novel predictive biomarker of poor progression-free survival and chemoresistance in metastatic lung cancer. J Cancer. 2021;12(19):5723-31.
31. Sun W, Zhang Y, Liu B, Duan Y, Li W, Chen J. Gene Polymorphism of MUC15, MMP14, BRAF, and COL1A1 Is Associated with Capsule Formation in Hepatocellular Carcinoma. Can J Gastroenterol Hepatol. 2021;2021:9990305.
32. Abdel-Maksoud MA, Ullah S, Nadeem A, Shaikh A, Zia MK, Zakri AM, et al. Unlocking the diagnostic, prognostic roles, and immune implications of BAX gene expression in pan-cancer analysis. American Journal of Translational Research. 2024;16(1):63.
33. Geng Q, Shen Z, Li L, Zhao J. COL1A1 is a prognostic biomarker and correlated with immune infiltrates in lung cancer. PeerJ. 2021;9:e11145.
34. Huang L, Irshad S, Sultana U, Ali S, Jamil A, Zubair A, et al. Pan-cancer analysis of HS6ST2: associations with prognosis, tumor immunity, and drug resistance. American Journal of Translational Research. 2024;16(3):873.
35. Ma H-P, Chang H-L, Bamodu OA, Yadav VK, Huang T-Y, Wu ATH, et al. Collagen 1A1 (COL1A1) Is a Reliable Biomarker and Putative Therapeutic Target for Hepatocellular Carcinogenesis and Metastasis. Cancers. 2019;11(6):786.
36. Lin ZY, Chuang WL. Genes responsible for the characteristics of primary cultured invasive phenotype hepatocellular carcinoma cells. Biomed Pharmacother. 2012 Sep;66(6):454-8.
37. Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi BV, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19(8):649-58.
38. Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic acids research. 2017;45(W1):W98-W102.
39. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Science signaling. 2013;6(269):pl1-pl.
40. Lánczky A, Győrffy B. Web-Based Survival Analysis Tool Tailored for Medical Research (KMplot): Development and Implementation. J Med Internet Res. 2021 Jul 26;23(7):e27633.
41. Wu W, He X, Andayani D, Yang L, Ye J, Li Y, et al. Pattern of distant extrahepatic metastases in primary liver cancer: a SEER based study. Journal of Cancer. 2017;8(12):2312.
42. Chen S, Gao Y, Li Z, Fang M, Wang M, Feng H, et al. A nomogram predicting extrahepatic metastases for patients with adjuvant transarterial chemoembolization after hepatectomy. Journal of Cancer. 2018;9(22):4223.
43. Ochiai T, Ikoma H, Okamoto K, Kokuba Y, Sonoyama T, Otsuji E. Clinicopathologic features and risk factors for extrahepatic recurrences of hepatocellular carcinoma after curative resection. World journal of surgery. 2012;36(1):136-43.
44. Fernandez-Pineda I, Sandoval JA, Davidoff AM. Hepatic metastatic disease in pediatric and adolescent solid tumors. World journal of hepatology. 2015;7(14):1807.
45. Marini JC, Cabral WA. Osteogenesis imperfecta. Genetics of bone biology and skeletal disease. 2018:397-420.
46. Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. Journal of cell biology. 2012;196(4):395-406.
47. Li B, Severson E, Pignon J-C, Zhao H, Li T, Novak J, et al. Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome biology. 2016;17:1-16.
48. Liu J, Shen J-X, Wu H-T, Li X-L, Wen X-F, Du C-W, et al. Collagen 1A1 (COL1A1) promotes metastasis of breast cancer and is a potential therapeutic target. Discovery medicine. 2018;25(139):211-23.
49. Oleksiewicz U, Liloglou T, Tasopoulou K-M, Daskoulidou N, Gosney JR, Field JK, et al. COL1A1, PRPF40A, and UCP2 correlate with hypoxia markers in non-small cell lung cancer. Journal of cancer research and clinical oncology. 2017;143:1133-41.
50. Jiang K, Liu H, Xie D, Xiao Q. Differentially expressed genes ASPN, COL1A1, FN1, VCAN and MUC5AC are potential prognostic biomarkers for gastric cancer. Oncol Lett. 2019 Mar;17(3):3191-202.