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An integrated analysis identifies STAT4 as a key regulator of ovarian cancer metastasis

Oncogene volume 36, pages 3384–3396 (2017)Cite this article

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Abstract

Epithelial ovarian cancer (EOC) is one of the most common gynecological cancers, with diagnosis often at a late stage. Metastasis is a major cause of death in patients with EOC, but the underlying molecular mechanisms remain obscure. Here, we utilized an integrated approach to find potential key transcription factors involved in ovarian cancer metastasis and identified STAT4 as a critical player in ovarian cancer metastasis. We found that activated STAT4 was overexpressed in epithelial cells of ovarian cancer and STAT4 overexpression was associated with poor outcome of ovarian cancer patients, which promoted metastasis of ovarian cancer in both in vivo and in vitro. Although STAT4 mediated EOC metastasis via inducing epithelial-to-mesenchymal transition (EMT) of ovarian cancer cells in vivo, STAT4 failed to induce EMT directly in vitro, suggesting that STAT4 might mediate EMT process via cancer–stroma interactions. Further functional analysis revealed that STAT4 overexpression induced normal omental fibroblasts and adipose- and bone marrow-derived mesenchymal stem cells to obtain cancer-associated fibroblasts (CAF)-like features via induction of tumor-derived Wnt7a. Reciprocally, increased production of CAF-induced CXCL12, IL6 and VEGFA within tumor microenvironment could enable peritoneal metastasis of ovarian cancer via induction of EMT program. In summary, our study established a model that STAT4 promotes ovarian cancer metastasis via tumor-derived Wnt7a-induced activation of CAFs.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (grant #81402396), Sichuan Science-Technology Soft Sciences Project (grant #2016ZR0086), Yi Yao Foundation (grant #14H0563) and Direct Scientific Research Grants from West China Second Hospital, Sichuan University (grant #KS021).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second Hospital and State Key Laboratory of Biotherapy/Collaborative Innovation Center, West China Hospital, Sichuan University, Chengdu, China

    L Zhao, G Ji, X Le, Y Zhang, Y Xuan, T Yi, S Yao, X Zhao, Y Wei & S Zhou

  2. College of Biological Sciences, Sichuan University, Chengdu, China

    Z Luo & C Wang

  3. Department of Pathology, West China Second Hospital, Sichuan University, Chengdu, China

    M Feng & L Xu

  4. Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, USA

    W B Lau

  5. Department of Surgery, Emergency Medicine, Kaiser Santa Clara Medical Center, Affiliate of Stanford University, Santa Clara, CA, USA

    B Lau

  6. West China School of Medicine, Sichuan University, Chengdu, China

    Y Yang & L Lei

  7. Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, China

    H Yang

  8. Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China

    Y Chen & X Deng

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  1. L Zhao
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  2. G Ji
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Correspondence to S Zhou.

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Cite this article

Zhao, L., Ji, G., Le, X. et al. An integrated analysis identifies STAT4 as a key regulator of ovarian cancer metastasis. Oncogene 36, 3384–3396 (2017). https://doi.org/10.1038/onc.2016.487

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  • DOI: https://doi.org/10.1038/onc.2016.487

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