Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2020

01-12-2020 | Metastasis | Research

COL4A1 promotes the growth and metastasis of hepatocellular carcinoma cells by activating FAK-Src signaling

Authors: Ting Wang, Haojie Jin, Jingying Hu, Xi Li, Haoyu Ruan, Huili Xu, Lin Wei, Weihua Dong, Fei Teng, Jianren Gu, Wenxin Qin, Xiaoying Luo, Yujun Hao

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2020

Login to get access

Abstract

Background

Collagens are the most abundant proteins in extra cellular matrix and important components of tumor microenvironment. Recent studies have showed that aberrant expression of collagens can influence tumor cell behaviors. However, their roles in hepatocellular carcinoma (HCC) are poorly understood.

Methods

In this study, we screened all 44 collagen members in HCC using whole transcriptome sequencing data from the public datasets, and collagen type IV alpha1 chain (COL4A1) was identified as most significantly differential expressed gene. Expression of COL4A1 was detected in HCC samples by quantitative real-time polymerase chain reaction (qRT-PCR), western blot and immunohistochemistry (IHC). Finally, functions and potential mechanisms of COL4A1 were explored in HCC progression.

Results

COL4A1 is the most significantly overexpressed collagen gene in HCC. Upregulation of COL4A1 facilitates the proliferation, migration and invasion of HCC cells through FAK-Src signaling. Expression of COL4A1 is upregulated by RUNX1 in HCC. HCC cells with high COL4A1 expression are sensitive to the treatment with FAK or Src inhibitor.

Conclusion

COL4A1 facilitates growth and metastasis in HCC via activation of FAK-Src signaling. High level of COL4A1 may be a potential biomarker for diagnosis and treatment with FAK or Src inhibitor for HCC.
Appendix
Available only for authorised users
Literature
1.
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 Cancer J Clin. 2018;68:394–424.
2.
Cadier B, Bulsei J, Nahon P, Seror O, Laurent A, Rosa I, et al. Early detection and curative treatment of hepatocellular carcinoma: a cost-effectiveness analysis in France and in the United States. Hepatology. 2017;65:1237–48.PubMed
3.
Thomas MB, Zhu AX. Hepatocellular carcinoma: the need for progress. J Clin Oncol. 2005;23:2892–9.PubMed
4.
Thangavelu PU, Krenács T, Dray E, Duijf PHG. In epithelial cancers, aberrant COL17A1 promoter methylation predicts its misexpression and increased invasion. Clin Epigenetics. 2016;8:120-32.
5.
Fang M, Yuan J, Peng C, Li Y. Collagen as a double-edged sword in tumor progression. Tumour Biol. 2014;35:2871–82.PubMed
6.
Jarvelainen H, Sainio A, Koulu M, Wight TN, Penttinen R. Extracellular matrix molecules: potential targets in pharmacotherapy. Pharmacol Rev. 2009;61:198–223.PubMedPubMedCentral
7.
Alex L, Frangogiannis NG. The cellular origin of activated fibroblasts in the infarcted and remodeling myocardium. Circ Res. 2018;122:540–2.PubMedPubMedCentral
8.
Hosaki-Takamiya R, Hashimoto M, Imai Y, Nishida T, Yamada N, Mori H, et al. Collagen production of osteoblasts revealed by ultra-high voltage electron microscopy. J Bone Miner Metab. 2016;34:491–9.PubMed
9.
Buchtler S, Grill A, Hofmarksrichter S, Stockert P, Schiechl-Brachner G, Rodriguez GM, et al. Cellular origin and functional relevance of collagen I production in the kidney. J Am Soc Nephrol. 2018;29:1859–73.PubMedPubMedCentral
10.
Wang H, Su Y. Collagen IV contributes to nitric oxide-induced angiogenesis of lung endothelial cells. Am J Physiol Cell Physiol. 2011;300:C979–88.PubMedPubMedCentral
11.
Abrahamson DR, Hudson BG, Stroganova L, Borza DB, St JP. Cellular origins of type IV collagen networks in developing glomeruli. J Am Soc Nephrol. 2009;20:1471–9.PubMedPubMedCentral
12.
Xu S, Xu H, Wang W, Li S, Li H, Li T, et al. The role of collagen in cancer: from bench to bedside. J Transl Med. 2019;17:309.PubMedPubMedCentral
13.
Brooks M, Mo Q, Krasnow R, Ho PL, Lee YC, Xiao J, et al. Positive association of collagen type I with non-muscle invasive bladder cancer progression. Oncotarget. 2016;7:82609–19.PubMedPubMedCentral
14.
Barcus CE, O'Leary KA, Brockman JL, Rugowski DE, Liu Y, Garcia N, et al. Elevated collagen-I augments tumor progressive signals, intravasation and metastasis of prolactin-induced estrogen receptor alpha positive mammary tumor cells. Breast Cancer Res. 2017;19:9.PubMedPubMedCentral
15.
Shintani Y, Maeda M, Chaika N, Johnson KR, Wheelock MJ. Collagen I promotes epithelial-to-mesenchymal transition in lung cancer cells via transforming growth factor-beta signaling. Am J Respir Cell Mol Biol. 2008;38:95–104.PubMed
16.
Shintani Y, Hollingsworth MA, Wheelock MJ, Johnson KR. Collagen I promotes metastasis in pancreatic cancer by activating c-Jun NH (2)-terminal kinase 1 and up-regulating N-cadherin expression. Cancer Res. 2006;66:11745–53.PubMed
17.
Yang MC, Wang CJ, Liao PC, Yen CJ, Shan YS. Hepatic stellate cells secretes type I collagen to trigger epithelial mesenchymal transition of hepatoma cells. Am J Cancer Res. 2014;4:751–63.PubMedPubMedCentral
18.
Nystrom H, Naredi P, Hafstrom L, Sund M. Type IV collagen as a tumour marker for colorectal liver metastases. Eur J Surg Oncol. 2011;37:611–7.PubMed
19.
Nystrom H, Tavelin B, Bjorklund M, Naredi P, Sund M. Improved tumour marker sensitivity in detecting colorectal liver metastases by combined type IV collagen and CEA measurement. Tumour Biol. 2015;36:9839–47.PubMedPubMedCentral
20.
Qiao J, Fang CY, Chen SX, Wang XQ, Cui SJ, Liu XH, et al. Stroma derived COL6A3 is a potential prognosis marker of colorectal carcinoma revealed by quantitative proteomics. Oncotarget. 2015;6:29929–46.PubMedPubMedCentral
21.
Sherman-Baust CA, Weeraratna AT, Rangel LB, Pizer ES, Cho KR, Schwartz DR, et al. Remodeling of the extracellular matrix through overexpression of collagen VI contributes to cisplatin resistance in ovarian cancer cells. Cancer Cell. 2003;3:377–86.PubMed
22.
An JH, Lee SY, Jeon JY, Cho KG, Kim SU, Lee MA. Identification of gliotropic factors that induce human stem cell migration to malignant tumor. J Proteome Res. 2009;8:2873–81.PubMed
23.
Fischer H, Salahshor S, Stenling R, Bjork J, Lindmark G, Iselius L, et al. COL11A1 in FAP polyps and in sporadic colorectal tumors. BMC Cancer. 2001;1:17.PubMedPubMedCentral
24.
Cheon DJ, Tong Y, Sim MS, Dering J, Berel D, Cui X, et al. A collagen-remodeling gene signature regulated by TGF-beta signaling is associated with metastasis and poor survival in serous ovarian cancer. Clin Cancer Res. 2014;20:711–23.PubMed
25.
Halsted KC, Bowen KB, Bond L, Luman SE, Jorcyk CL, Fyffe WE, et al. Collagen alpha1(XI) in normal and malignant breast tissue. Mod Pathol. 2008;21:1246–54.PubMedPubMedCentral
26.
Stelkovics E, Korom I, Marczinovits I, Molnar J, Rasky K, Raso E, et al. Collagen XVII/BP180 protein expression in squamous cell carcinoma of the skin detected with novel monoclonal antibodies in archived tissues using tissue microarrays and digital microscopy. Appl Immunohistochem Mol Morphol. 2008;16:433–41.PubMed
27.
Krenacs T, Kiszner G, Stelkovics E, Balla P, Teleki I, Nemeth I, et al. Collagen XVII is expressed in malignant but not in benign melanocytic tumors and it can mediate antibody induced melanoma apoptosis. Histochem Cell Biol. 2012;138:653–67.PubMed
28.
Kalluri R. Basement membranes: structure, assembly and role in tumour angiogenesis. Nat Rev Cancer. 2003;3:422–33.PubMed
29.
Karsdal MA, Nielsen SH, Leeming DJ, Langholm LL, Nielsen MJ, Manon-Jensen T, et al. The good and the bad collagens of fibrosis - their role in signaling and organ function. Adv Drug Deliv Rev. 2017;121:43–56.PubMed
30.
Li T, Leng XS, Zhu JY, Wang G. Suppression of hedgehog signaling regulates hepatic stellate cell activation and collagen secretion. Int J Clin Exp Pathol. 2015;8:14574–9.PubMedPubMedCentral
31.
Kuo DS, Labelle-Dumais C, Gould DB. COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets. Hum Mol Genet. 2012;21:R97–110.PubMedPubMedCentral
32.
Gould DB, Phalan FC, Breedveld GJ, van Mil SE, Smith RS, Schimenti JC, et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science. 2005;308:1167–71.PubMed
33.
Plaisier E, Gribouval O, Alamowitch S, Mougenot B, Prost C, Verpont MC, et al. COL4A1 mutations and hereditary angiopathy, nephropathy, aneurysms, and muscle cramps. N Engl J Med. 2007;357:2687–95.PubMed
34.
Labelle-Dumais C, Dilworth DJ, Harrington EP, de Leau M, Lyons D, Kabaeva Z, et al. COL4A1 mutations cause ocular dysgenesis, neuronal localization defects, and myopathy in mice and Walker-Warburg syndrome in humans. PLoS Genet. 2011;7:e1002062.PubMedPubMedCentral
35.
Miyake M, Hori S, Morizawa Y, Tatsumi Y, Toritsuka M, Ohnishi S, et al. Collagen type IV alpha 1 (COL4A1) and collagen type XIII alpha 1 (COL13A1) produced in cancer cells promote tumor budding at the invasion front in human urothelial carcinoma of the bladder. Oncotarget. 2017;8:36099.PubMedPubMedCentral
36.
Jin R, Shen J, Zhang T, Liu Q, Liao C, Ma H, et al. The highly expressed COL4A1 genes contributes to the proliferation and migration of the invasive ductal carcinomas. Oncotarget. 2017;8:58172–83.PubMedPubMedCentral
37.
Jin H, Wang C, Jin G, Ruan H, Gu D, Wei L, et al. Regulator of Calcineurin 1 gene isoform 4, Down-regulated in hepatocellular carcinoma, prevents proliferation, migration, and invasive activity of Cancer cells and metastasis of Orthotopic tumors by inhibiting nuclear translocation of NFAT1. Gastroenterology. 2017;153:799–811.PubMed
38.
39.
Pollner R, Schmidt C, Fischer G, Kuhn K, Poschl E. Cooperative and competitive interactions of regulatory elements are involved in the control of divergent transcription of human Col4A1 and Col4A2 genes. FEBS Lett. 1997;405:31–6.PubMed
40.
Ma HP, Chang HL, Bamodu OA, Yadav VK, Huang TY, Wu A, et al. Collagen 1A1 (COL1A1) Is a Reliable Biomarker and Putative Therapeutic Target for Hepatocellular Carcinogenesis and Metastasis. Cancers (Basel). 2019;11:768-800.
41.
Zheng X, Liu W, Xiang J, Liu P, Ke M, Wang B, et al. Collagen I promotes hepatocellular carcinoma cell proliferation by regulating integrin beta1/FAK signaling pathway in nonalcoholic fatty liver. Oncotarget. 2017;8:95586–95.PubMedPubMedCentral
42.
Zheng Q, Zhou G, Morello R, Chen Y, Garcia-Rojas X, Lee B. Type X collagen gene regulation by Runx2 contributes directly to its hypertrophic chondrocyte-specific expression in vivo. J Cell Biol. 2003;162:833–42.PubMedPubMedCentral
43.
Higashikawa A, Saito T, Ikeda T, Kamekura S, Kawamura N, Kan A, et al. Identification of the core element responsive to runt-related transcription factor 2 in the promoter of human type X collagen gene. Arthritis Rheum. 2009;60:166–78.PubMed
44.
Wei J, Shimazu J, Makinistoglu MP, Maurizi A, Kajimura D, Zong H, et al. Glucose uptake and Runx2 synergize to orchestrate osteoblast differentiation and bone formation. Cell. 2015;161:1576–91.PubMedPubMedCentral
45.
46.
Chen SY, Lin JS, Yang BC. Modulation of tumor cell stiffness and migration by type IV collagen through direct activation of integrin signaling pathway. Arch Biochem Biophys. 2014;555-556:1–8.PubMed
47.
Hodgson L, Henderson AJ, Dong C. Melanoma cell migration to type IV collagen requires activation of NF-kappaB. Oncogene. 2003;22:98–108.PubMedPubMedCentral
48.
Macias-Perez I, Borza C, Chen X, Yan X, Ibanez R, Mernaugh G, et al. Loss of integrin alpha1beta1 ameliorates Kras-induced lung cancer. Cancer Res. 2008;68:6127–35.PubMedPubMedCentral
49.
Kim SH, Turnbull J, Guimond S. Extracellular matrix and cell signalling: the dynamic cooperation of integrin, proteoglycan and growth factor receptor. J Endocrinol. 2011;209:139–51.PubMed
50.
Bolos V, Gasent JM, Lopez-Tarruella S, Grande E. The dual kinase complex FAK-Src as a promising therapeutic target in cancer. Onco Targets Ther. 2010;3:83–97.PubMedPubMedCentral
51.
Mitra SK, Schlaepfer DD. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol. 2006;18:516–23.PubMed
52.
Mitra SK, Hanson DA, Schlaepfer DD. Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol. 2005;6:56–68.PubMed
53.
Espinosa NR, Salazar EP. Native type IV collagen induces an epithelial to mesenchymal transition-like process in mammary epithelial cells MCF10A. Int J Biochem Cell Biol. 2012;44:2194–203.
54.
Cortes-Reynosa P, Robledo T, Macias-Silva M, Wu SV, Salazar EP. Src kinase regulates metalloproteinase-9 secretion induced by type IV collagen in MCF-7 human breast cancer cells. Matrix Biol. 2008;27:220–31.PubMed
55.
Papaioannou I, Xu S, Denton CP, Abraham DJ, Ponticos M. STAT3 controls COL1A2 enhancer activation cooperatively with JunB, regulates type I collagen synthesis posttranscriptionally, and is essential for lung myofibroblast differentiation. Mol Biol Cell. 2018;29:84–95.PubMedPubMedCentral
56.
Liu Y, Zhang J, Chen Y, Sohel H, Ke X, Chen J, et al. The correlation and role analysis of COL4A1 and COL4A2 in hepatocarcinogenesis. Aging (Albany NY). 2020;12:204–23.
57.
Burnier JV, Wang N, Michel RP, Hassanain M, Li S, Lu Y, et al. Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis. Oncogene. 2011;30:3766–83.PubMed
58.
Otalora-Otalora BA, Henriquez B, Lopez-Kleine L, Rojas A. RUNX family: oncogenes or tumor suppressors (review). Oncol Rep. 2019;42:3–19.PubMedPubMedCentral
59.
Yamagata T, Maki K, Mitani K. Runx1/AML1 in normal and abnormal hematopoiesis. Int J Hematol. 2005;82:1–8.PubMed
60.
Sengupta S, den Boon JA, Chen IH, Newton MA, Stanhope SA, Cheng YJ, et al. MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins. Proc Natl Acad Sci U S A. 2008;105:5874–8.PubMedPubMedCentral
61.
Du B, Ma LM, Huang MB, Zhou H, Huang HL, Shao P, et al. High glucose down-regulates miR-29a to increase collagen IV production in HK-2 cells. FEBS Lett. 2010;584:811–6.PubMed
62.
63.
Scheitz CJ, Lee TS, McDermitt DJ, Tumbar T. Defining a tissue stem cell-driven Runx1/Stat3 signalling axis in epithelial cancer. EMBO J. 2012;31:4124–39.PubMedPubMedCentral
64.
Keita M, Bachvarova M, Morin C, Plante M, Gregoire J, Renaud MC, et al. The RUNX1 transcription factor is expressed in serous epithelial ovarian carcinoma and contributes to cell proliferation, migration and invasion. Cell Cycle. 2013;12:972–86.PubMedPubMedCentral
65.
Nie Y, Zhou L, Wang H, Chen N, Jia L, Wang C, et al. Profiling the epigenetic interplay of lncRNA RUNXOR and oncogenic RUNX1 in breast cancer cells by gene in situ cis-activation. Am J Cancer Res. 2019;9:1635–49.PubMedPubMedCentral
66.
Cheng CK, Wong T, Wan T, Wang AZ, Chan N, Chan N, et al. RUNX1 upregulation via disruption of long-range transcriptional control by a novel t (5;21)(q13;q22) translocation in acute myeloid leukemia. Mol Cancer. 2018;17:133.PubMedPubMedCentral
Metadata
Title
COL4A1 promotes the growth and metastasis of hepatocellular carcinoma cells by activating FAK-Src signaling
Authors
Ting Wang
Haojie Jin
Jingying Hu
Xi Li
Haoyu Ruan
Huili Xu
Lin Wei
Weihua Dong
Fei Teng
Jianren Gu
Wenxin Qin
Xiaoying Luo
Yujun Hao
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2020
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-020-01650-7

Other articles of this Issue 1/2020

Journal of Experimental & Clinical Cancer Research 1/2020 Go to the issue

Research

Monocyte Chemoattractant Protein-1 promotes cancer cell migration via c-Raf/MAPK/AP-1 pathway and MMP-9 production in osteosarcoma

Research

Promotion of ubiquitination-dependent survivin destruction contributes to xanthohumol-mediated tumor suppression and overcomes radioresistance in human oral squamous cell carcinoma

Review

Glycometabolic rearrangements--aerobic glycolysis in pancreatic cancer: causes, characteristics and clinical applications

Research

Circ_0008532 promotes bladder cancer progression by regulation of the miR-155-5p/miR-330-5p/MTGR1 axis

Research

HIF-1α-dependent miR-424 induction confers cisplatin resistance on bladder cancer cells through down-regulation of pro-apoptotic UNC5B and SIRT4

Research

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits