Abstract
Biomarkers that predict disease progression might assist the development of better therapeutic strategies for aggressive cancers, such as ovarian cancer. Here, we investigated the role of collagen type XI alpha 1 (COL11A1) in cell invasiveness and tumor formation and the prognostic impact of COL11A1 expression in ovarian cancer. Microarray analysis suggested that COL11A1 is a disease progression-associated gene that is linked to ovarian cancer recurrence and poor survival. Small interference RNA-mediated specific reduction in COL11A1 protein levels suppressed the invasive ability and oncogenic potential of ovarian cancer cells and decreased tumor formation and lung colonization in mouse xenografts. A combination of experimental approaches, including real-time RT–PCR, casein zymography and chromatin immunoprecipitation (ChIP) assays, showed that COL11A1 knockdown attenuated MMP3 expression and suppressed binding of Ets-1 to its putative MMP3 promoter-binding site, suggesting that the Ets-1–MMP3 axis is upregulated by COL11A1. Transforming growth factor (TGF)-beta (TGF-β1) treatment triggers the activation of smad2 signaling cascades, leading to activation of COL11A1 and MMP3. Pharmacological inhibition of MMP3 abrogated the TGF-β1-triggered, COL11A1-dependent cell invasiveness. Furthermore, the NF-YA-binding site on the COL11A1 promoter was identified as the major determinant of TGF-β1-dependent COL11A1 activation. Analysis of 88 ovarian cancer patients indicated that high COL11A1 mRNA levels are associated with advanced disease stage. The 5-year recurrence-free and overall survival rates were significantly lower (P=0.006 and P=0.018, respectively) among patients with high expression levels of tissue COL11A1 mRNA compared with those with low expression. We conclude that COL11A1 may promote tumor aggressiveness via the TGF-β1–MMP3 axis and that COL11A1 expression can predict clinical outcome in ovarian cancer patients.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Jemal A, Thomas A, Murray T, Thun M . Cancer statistics, 2002. CA Cancer J Clin 2002; 52: 23–47.
Agarwal R, Kaye SB . Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer 2003; 3: 502–516.
Steeg PS . Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 2006; 12: 895–904.
Bjorklund M, Koivunen E . Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta 2005; 1755: 37–69.
Curran S, Murray GI . Matrix metalloproteinases in tumour invasion and metastasis. J Pathol 1999; 189: 300–308.
Guo W, Giancotti FG . Integrin signalling during tumour progression. Nat Rev Mol Cell Biol 2004; 5: 816–826.
Peinado H, Portillo F, Cano A . Transcriptional regulation of cadherins during development and carcinogenesis. Int J Dev Biol 2004; 48: 365–375.
Vleminckx K, Vakaet L Jr, Mareel M, Fiers W, van Roy F . Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role. Cell 1991; 66: 107–119.
Schwartz DR, Kardia SL, Shedden KA, Kuick R, Michailidis G, Taylor JM et al. Gene expression in ovarian cancer reflects both morphology and biological behavior, distinguishing clear cell from other poor-prognosis ovarian carcinomas. Cancer Res 2002; 62: 4722–4729.
Zorn KK, Bonome T, Gangi L, Chandramouli GV, Awtrey CS, Gardner GJ et al. Gene expression profiles of serous, endometrioid, and clear cell subtypes of ovarian and endometrial cancer. Clin Cancer Res 2005; 11: 6422–6430.
Shridhar V, Lee J, Pandita A, Iturria S, Avula R, Staub J et al. Genetic analysis of early- versus late-stage ovarian tumors. Cancer Res 2001; 61: 5895–5904.
Berchuck A, Iversen ES, Lancaster JM, Pittman J, Luo J, Lee P et al. Patterns of gene expression that characterize long-term survival in advanced stage serous ovarian cancers. Clin Cancer Res 2005; 11: 3686–3696.
Spentzos D, Levine DA, Ramoni MF, Joseph M, Gu X, Boyd J et al. Gene expression signature with independent prognostic significance in epithelial ovarian cancer. J Clin Oncol 2004; 22: 4700–4710.
Tothill RW, Tinker AV, George J, Brown R, Fox SB, Lade S et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res 2008; 14: 5198–5208.
Jazaeri AA, Awtrey CS, Chandramouli GV, Chuang YE, Khan J, Sotiriou C et al. Gene expression profiles associated with response to chemotherapy in epithelial ovarian cancers. Clin Cancer Res 2005; 11: 6300–6310.
Hartmann LC, Lu KH, Linette GP, Cliby WA, Kalli KR, Gershenson D et al. Gene expression profiles predict early relapse in ovarian cancer after platinum-paclitaxel chemotherapy. Clin Cancer Res 2005; 11: 2149–2155.
Konstantinopoulos PA, Spentzos D, Karlan BY, Taniguchi T, Fountzilas E, Francoeur N et al. Gene expression profile of BRCAness that correlates with responsiveness to chemotherapy and with outcome in patients with epithelial ovarian cancer. J Clin Oncol 2010; 28: 3555–3561.
Boudreau N, Bissell MJ . Extracellular matrix signaling: integration of form and function in normal and malignant cells. Curr Opin Cell Biol 1998; 10: 640–646.
Stracke ML, Murata J, Aznavoorian S, Liotta LA . The role of the extracellular matrix in tumor cell metastasis. In Vivo 1994; 8: 49–58.
Fischer H, Stenling R, Rubio C, Lindblom A . Colorectal carcinogenesis is associated with stromal expression of COL11A1 and COL5A2. Carcinogenesis 2001; 22: 875–878.
Chong IW, Chang MY, Chang HC, Yu YP, Sheu CC, Tsai JR et al. Great potential of a panel of multiple hMTH1, SPD, ITGA11 and COL11A1 markers for diagnosis of patients with non-small cell lung cancer. Oncol Rep 2006; 16: 981–988.
Dennis G Jr, Sherman BT, Hosack DA, Yang J, Gao W, Lane HC et al. DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol 2003; 4: P3.
Belotti D, Paganoni P, Manenti L, Garofalo A, Marchini S, Taraboletti G et al. Matrix metalloproteinases (MMP9 and MMP2) induce the release of vascular endothelial growth factor (VEGF) by ovarian carcinoma cells: implications for ascites formation. Cancer Res 2003; 63: 5224–5229.
Leroy-Dudal J, Demeilliers C, Gallet O, Pauthe E, Dutoit S, Agniel R et al. Transmigration of human ovarian adenocarcinoma cells through endothelial extracellular matrix involves alphav integrins and the participation of MMP2. Int J Cancer 2005; 114: 531–543.
Kenny HA, Kaur S, Coussens LM, Lengyel E . The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin. J Clin Invest 2008; 118: 1367–1379.
Rae MT, Price D, Harlow CR, Critchley HO, Hillier SG . Glucocorticoid receptor-mediated regulation of MMP9 gene expression in human ovarian surface epithelial cells. Fertil Steril 2009; 92: 703–708.
Choi JW, Ahn SE, Rengaraj D, Seo HW, Lim W, Song G et al. Matrix metalloproteinase 3 is a stromal marker for chicken ovarian cancer. Oncol Lett 2011; 2: 1047–1051.
Horváth B, Hegyesi H, Nagy P, Falus A, Schaff Z . Expression of ets-1 transcription factor in human head and neck squamous cell carcinoma and effect of histamine on metastatic potential of invasive tumor through the regulation of expression of ets-1 and matrix metalloproteinase-3. Head Neck 2005; 27: 585–596.
Gaspar NJ, Li L, Kapoun AM, Medicherla S, Reddy M, Li G et al. Inhibition of transforming growth factor beta signaling reduces pancreatic adenocarcinoma growth and invasiveness. Mol Pharmacol 2007; 72: 152–161.
Matsuo N, Yu-Hua W, Sumiyoshi H, Sakata-Takatani K, Nagato H, Sakai K et al. The transcription factor CCAAT-binding factor CBF/NF-Y regulates the proximal promoter activity in the human alpha 1(XI) collagen gene (COL11A1). J Biol Chem 2003; 278: 32763–32770.
Alabert C, Rogers L, Kahn L, Niellez S, Fafet P, Cerulis S et al. Cell type-dependent control of NF-Y activity by TGF-beta. Oncogene 2006; 25: 3387–3396.
Kim H, Watkinson J, Varadan V, Anastassiou D . Multi-cancer computational analysis reveals invasion-associated variant of desmoplastic reaction involving INHBA, THBS2 and COL11A1. BMC Medical Genomics 2010; 3: 51.
Knudsen ES, Ertel A, Davicioni E, Kline J, Schwartz GF, Witkiewicz AK . Progression of ductal carcinoma in situ to invasive breast cancer is associated with gene expression program of EMT and myoepithelia. Breast Cancer Res Treat 2012; 133: 1009–1024.
Turashvili G, Bouchal J, Baumforth K, Wei W, Dziechciarkova M, Ehrmann J et al. Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis. BMC Cancer 2007; 7: 55.
Schuetz CS, Bonin M, Clare SE, Nieselt K, Sotlar K, Walter M et al. Progression-specific genes identified by expression profiling of matched ductal carcinomas in situ and invasive breast tumors, combining laser capture microdissection and oligonucleotide microarray analysis. Cancer Res 2006; 66: 5278–5286.
Bowen KB, Reimers AP, Luman S, Kronz JD, Fyffe WE, Oxford JT . Immunohistochemical localization of collagen type XI alpha 1 and alpha 2 chains in human colon tissue. J Histochem Cytochem 2008; 56: 275–283.
Fisher 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.
Bedea L, Herlea V, Dima SO, Dumitrascu T, Popescu I . Combined gene expression analysis of whole-tissue and microdissected pancreatic ductal adenocarcinoma identifies genes specifically overexpressed in tumor epithelia. Hepatogastroenterology 2008; 55: 2016–2027.
Vecchi M, Nuciforo P, Romagnoli S, Confalonieri S, Pellegrini C, Serio G et al. Gene expression analysis of early and advanced gastric cancers. Oncogene 2007; 26: 4284–4294.
Schmalbach CE, Chepeha DB, Giordano TJ, Rubin MA, Teknos TN, Bradford CR et al. Molecular profiling and the identification of genes associated with metastatic oral cavity/pharynx squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 2004; 130: 295–302.
Khatun S, Fujimoto J, Toyoki H, Tamaya T . Clinical implications of expression of ETS-1 in relation to angiogenesis in ovarian cancers. Cancer Sci 2003; 94: 769–773.
Nakayama T, Ito M, Ohtsuru A, Naito S, Nakashima M, Fagin JA et al. Expression of the ets-1 proto-oncogene in human gastric carcinoma: correlation with tumor invasion. Am J Pathol 1996; 149: 1931–1939.
Ito T, Nakayama T, Ito M, Naito S, Kanematsu T, Sekine I . Expression of the ets-1 proto-oncogene in human pancreatic carcinoma. Mod Pathol 1998; 11: 209–215.
Saeki H, Kuwano H, Kawaguchi H, Ohno S, Sugimachi K . Expression of ets-1 transcription factor is correlated with penetrating tumor progression in patients with squamous cell carcinoma of the esophagus. Cancer 2000; 89: 1670–1676.
Ito Y, Miyoshi E, Takeda T, Sakon M, Noda K, Tsujimoto M et al. Expression and possible role of ets-1 in hepatocellular carcinoma. Am J Clin Pathol 2000; 114: 719–725.
Ozaki I, Mizuta T, Zhao G, Yotsumoto H, Hara T, Kajihara S et al. Involvement of the ets-1 gene in overexpression of matrilysin in human hepatocellular carcinoma. Cancer Res 2000; 60: 6519–6525.
Ito Y, Miyoshi E, Takeda T, Sakon M, Tsujimoto M, Yokosaki Y et al. Ets-1 expression in extrahepatic bile duct carcinoma and cholangiocellular carcinoma. Oncology 2000; 58: 248–252.
Nakayama T, Ito M, Ohtsuru A, Naito S, Nakashima M, Sekine I . Expression of the ets-1 proto-oncogene in human thyroid tumor. Mod Pathol 1999; 12: 61–68.
Kitange G, Kishikawa M, Nakayama T, Naito S, Iseki M, Shibata S . Expression of the Ets-1 proto-oncogene correlates with malignant potential in human astrocytic tumors. Mod Pathol 1999; 12: 618–626.
Oda N, Abe M, Sato Y . ETS-1 converts endothelial cells to the angiogenic phenotype by inducing the expression of matrix metalloproteinases and integrin beta3. J Cell Physiol 1999; 178: 121–132.
Sato Y, Abe M, Tanaka K, Iwasaka C, Oda N, Kanno S et al. Signal transduction and transcriptional regulation of angiogenesis. Adv Exp Med Biol 2000; 476: 109–115.
Derynck R, Akhurst RJ, Balmain A . TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 2001; 29: 117–129.
Padua D, Massague J . Roles of TGF beta in metastasis. Cell Res 2009; 19: 89–102.
Yamamura S, Matsumura N, Mandai M, Huang Z, Oura T, Baba T et al. The activated transforming growth factor-beta signaling pathway in peritoneal metastases is a potential therapeutic target in ovarian cancer. Int J Cancer 2012; 130: 20–28.
Hau P, Jachimczak P, Schlingensiepen R, Schulmeyer F, Jauch T, Steinbrecher A et al. Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies. Oligonucleotides 2007; 17: 201–212.
Gentleman R, Parman C, Halling C . affyQCReport: QC Report Generation for affyBatch objects 2005.
Gautier L, Cope L, Bolstad BM, Irizarry RA . affy—analysis of Affymetrix GeneChip data at the probe level. Bioinformatics 2004; 20: 307–315.
Wu YH, Wu TC, Liao JW, Yeh KT, Chen CY, Lee H . p53 dysfunction by xeroderma pigmentosum group C defects enhance lung adenocarcinoma metastasis via increased MMP1 expression. Cancer Res 2010; 70: 10422–10432.
Acknowledgements
This study was supported by ‘To establish centers of excellence for cancer research in Taiwan’ (DOH101-TD-C-111-003), Department of Health, Executive Yuan, Taiwan. This work was supported in part by National Science Council under Grant No.: NSC 101-2911-I-009-101, NSC 101-2311-B-009-003-MY3 and NSC 100-2627-B-009-002. The research was supported in part by Taipei Medical University under grant TMU101-AE1-B44.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Oncogene website
Rights and permissions
About this article
Cite this article
Wu, YH., Chang, TH., Huang, YF. et al. COL11A1 promotes tumor progression and predicts poor clinical outcome in ovarian cancer. Oncogene 33, 3432–3440 (2014). https://doi.org/10.1038/onc.2013.307
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2013.307
Keywords
This article is cited by
-
The downregulation of miR-509-3p expression by collagen type XI alpha 1-regulated hypermethylation facilitates cancer progression and chemoresistance via the DNA methyltransferase 1/Small ubiquitin-like modifier-3 axis in ovarian cancer cells
Journal of Ovarian Research (2023)
-
Mutant collagen COL11A1 enhances cancerous invasion
Oncogene (2021)
-
COL11A1 activates cancer-associated fibroblasts by modulating TGF-β3 through the NF-κB/IGFBP2 axis in ovarian cancer cells
Oncogene (2021)
-
Deep learning-based ovarian cancer subtypes identification using multi-omics data
BioData Mining (2020)
-
Inhibition of collagen XI alpha 1-induced fatty acid oxidation triggers apoptotic cell death in cisplatin-resistant ovarian cancer
Cell Death & Disease (2020)