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

• Published in: Oncogene 2017-06, Vol.36 (24), p.3384-3396
• Main Authors: Zhao, L, Ji, G, Le, X, Luo, Z, Wang, C, Feng, M, Xu, L, Zhang, Y, Lau, W B, Lau, B, Yang, Y, Lei, L, Yang, H, Xuan, Y, Chen, Y, Deng, X, Yi, T, Yao, S, Zhao, X, Wei, Y, Zhou, S
• Format: Article
• Language: English
• Subjects: 631/67/322; 692/53; 82/58; Animals; Apoptosis; Bone cancer; Bone marrow; Cancer metastasis; Cancer-Associated Fibroblasts - cytology; Cancer-Associated Fibroblasts - metabolism; Cancer-Associated Fibroblasts - pathology; Carcinoma, Ovarian Epithelial; Cell Biology; Cell Line, Tumor; CXCL12 protein; Death; Epithelial cells; Epithelial-Mesenchymal Transition; Female; Fibroblasts; Functional anatomy; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Human Genetics; Humans; Integrated approach; Interleukin 6; Internal Medicine; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Metastasis; Mice; Molecular modelling; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Glandular and Epithelial - metabolism; Neoplasms, Glandular and Epithelial - pathology; Oncology; original-article; Ovarian cancer; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - pathology; Peritoneum; Signal Transduction; STAT proteins; Stat4 protein; STAT4 Transcription Factor - metabolism; Stem cells; Stroma; Transcription factors; Tumor Microenvironment; Tumors; Up-Regulation; Wnt Proteins - metabolism
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.487

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.