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COL11A1 promotes tumor progression and predicts poor clinical outcome in ovarian cancer

Oncogene volume 33, pages 3432–3440 (2014)Cite this article

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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.

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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.

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  1. H-D Huang and C-Y Chou: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Research Center, National Cheng Kung University Hospital, Tainan, Taiwan, ROC

    Y-H Wu

  2. Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei, Taiwan, ROC

    T-H Chang

  3. Department of Obstetrics and Gynecology, College of Medicine, National Cheng Kung University and Hospital, Tainan, Taiwan, ROC

    Y-F Huang & C-Y Chou

  4. Department of Biological Science and Technology, National Chiao Tung University, Hsin Chu, Taiwan, ROC

    H-D Huang

  5. Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsin Chu, Taiwan, ROC

    H-D Huang

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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

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