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Interleukin-17 produced by tumor microenvironment promotes self-renewal of CD133+ cancer stem-like cells in ovarian cancer

Oncogene volume 34, pages 165–176 (2015)Cite this article

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Abstract

Inflammatory cytokines, components of cancer stem cells (CSCs) niche, could affect the characteristics of CSCs such as self-renewal and metastasis. Interleukin-17 (IL-17) is a new pro-inflammatory cytokine mainly produced by T-helper (Th17) cells and macrophages. The effects of IL-17 on the characteristics of CSCs remain to be explored. Here we first demonstrated a role of IL-17 in promoting the self-renewal of ovarian CD133+ cancer stem-like cells (CSLCs). We detected IL-17-producing cells (CD4+ cells and CD68+ macrophages) in the niche of CD133+CSLCs. Meanwhile, there was IL-17 receptor expression on CD133+CSLCs derived from A2780 cell line and primary ovarian cancer tissues. By recombinant human IL-17 stimulation and IL-17 transfection, the growth and sphere formation capacities of ovarian CD133+CSLCs were significantly enhanced in a dose-dependent manner. Moreover, ovarian CD133+CSLCs transfected with IL-17 showed greater tumorigenesis capacity in nude mice. These data suggest that IL-17 promoted the self-renewal of ovarian CD133+CSLCs. Further investigation through gene profiling revealed that the stimulation function of IL-17 on self-renewal of ovarian CD133+CSLCs might be mediated by the nuclear factor (NF)-κB and p38 mitogen-activated protein kinases (MAPK) signaling pathway. NF-κB and p38 MAPK were activated by IL-17. More importantly, IL-17-promoted self-renewal was inhibited by specific inhibitors of NF-κB and p38 MAPK. Taken together, our data indicate that IL-17 contributed to ovarian cancer malignancy through promoting the self-renewal of CD133+CSLCs and that IL-17 and its signaling pathway might serve as therapeutic targets for the treatment of ovarian cancer.

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Acknowledgements

This work was supported by National Nature Science Foundation of China (grant nos. 81070018, 81071772 and 81222031), by the outstanding Youth Scientist Foundation of Chongqing (no. CSTC, 2008BA5035) and by National Key Basic Research Program of China (973 program, grant nos. 2010CB529404 and 2012CB526603).

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  1. T Xiang and H Long: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China

    T Xiang, H Long, L He, X Han, K Lin, W Zhuo, R Xie & B Zhu

  2. Department of Obstetrics and Gynecology, Southwest Hospital, Third Military Medical University, Chongqing, China

    Z Liang

  3. Department of Obstetrics and Gynecology, Xinqiao Hospital, Third Military Medical University, Chongqing, China

    R Xie

  4. Biomedical Analysis Center, Third Military Medical University, Chongqing, China

    B Zhu

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Xiang, T., Long, H., He, L. et al. Interleukin-17 produced by tumor microenvironment promotes self-renewal of CD133+ cancer stem-like cells in ovarian cancer. Oncogene 34, 165–176 (2015). https://doi.org/10.1038/onc.2013.537

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