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COL11A1 activates cancer-associated fibroblasts by modulating TGF-β3 through the NF-κB/IGFBP2 axis in ovarian cancer cells

Oncogene volume 40, pages 4503–4519 (2021)Cite this article

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Abstract

Ovarian cancer has a unique tumor microenvironment (TME) that enables cancer-associated fibroblasts (CAFs) to interact with cellular and matrix constituents and influence tumor development and migration into the peritoneal cavity. Collagen type XI alpha 1 (COL11A1) is overexpressed in CAFs; therefore this study examines its role during CAF activation in epithelial ovarian cancer (EOC). Coculturing human ovarian fibroblasts (HOFs) with high COL11A1-expressing EOC cells or exposure to the conditioned medium of these cells prompted the expression of COL11A1 and CAF phenotypes. Conversely, coculturing HOFs with low COL11A1-expressing EOC cells or COL11A1-knockdown abrogated COL11A1 overexpression and secretion, in addition to CAF activation. Increased p-SP1 expression attributed to COL11A1-mediated extracellular signal-regulated kinase activation (ERK) induced p65 translocation into the nucleus and augmented its binding to the insulin-like growth factor binding protein 2 (IGFBP2) promoter, ultimately inducing TGF-β3 activation. The CAF–cancer cell crosstalk triggered interleukin-6 release, which in turn promoted EOC cell proliferation and invasiveness. These in vitro results were confirmed by in vivo findings in a mouse model, showing that COL11A1 overexpression in EOC cells promoted tumor formation and CAF activation, which was inhibited by TGF-β3 antibody. Human tumors with high TGF-β3 levels showed elevated expression of COL11A1 and IGFBP2, which was associated with poor survival. Our findings suggest the possibility that anti-TGF-β3 treatment strategy may be effective in targeting CAFs in COL11A1-positive ovarian tumors.

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Fig. 1: COL11A1 in EOC cells prompts normal HOFs to acquire CAF features and express COL11A1.
Fig. 2: CAF activation prompts HOF cell growth, invasive ability, and cell contraction.
Fig. 3: TGF-β3 is involved in COL11A1-induced CAF activation.
Fig. 4: COL11A1 regulates TGF-β3 through the NF-κB/IGFBP2 axis.
Fig. 5: CAFs activated by COL11A1 secrete IL-6 to promote ovarian cancer cell growth and invasion.
Fig. 6: COL11A1 promotes tumor formation and regulates CAF activation in vivo.
Fig. 7: Five-year overall survival and progression-free survival.

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Acknowledgements

This work was supported by grants from the National Science Council (MOST: No. 108-2314-B-384-011-MY3 and 108-2314-B-006-061-MY2). The study was also supported by grants from the Chi Mei Medical Center, Liouying Campus (CLFHR10822, CLFHR10911, CMLMOST10901, and CLFHR10921).

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Authors and Affiliations

  1. Department of Medical Research, Chi Mei Medical Center, Liouying, Tainan, Taiwan

    Yi-Hui Wu

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

    Yu-Fang Huang, Pei-Ying Wu & Cheng-Yang Chou

  3. Graduate Institute of Biomedical Informatics, Taipei Medical University, Taipei, Taiwan

    Tzu-Hao Chang

  4. Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan

    Chien-Chin Chen

  5. Department of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan, Taiwan

    Chien-Chin Chen

  6. Department of Obstetrics and Gynecology, Chi Mei Medical Center, Liouying, Tainan, Taiwan

    Soon-Cen Huang

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Wu, YH., Huang, YF., Chang, TH. et al. COL11A1 activates cancer-associated fibroblasts by modulating TGF-β3 through the NF-κB/IGFBP2 axis in ovarian cancer cells. Oncogene 40, 4503–4519 (2021). https://doi.org/10.1038/s41388-021-01865-8

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