IL-6R/STAT3/miR-204 feedback loop contributes to cisplatin resistance of epithelial ovarian cancer cells

// Xiaolan Zhu 1, 2, * , Huiling Shen 2, 3, * , Xinming Yin 1 , Lulu Long 3 , Xiaofang Chen 1 , Fan Feng 1 , Yueqin Liu 1 , Peiqing Zhao 2 , Yue Xu 1 , Mei Li 4 , Wenlin Xu 1 and Yuefeng Li 4 1 Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China 2 Jiangsu University, Medical School, Zhenjiang, Jiangsu 212003, China 3 Department of Oncology, The Affiliated People Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China 4 Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China * These authors are considered as co-first authors Correspondence to: Wenlin Xu, email: xwl630806@126.com Yuefeng Li, email: lxz1986122@sina.com Keywords: miR-204, IL-6R, STAT3, chemoresistance, EOC Received: January 23, 2017      Accepted: March 02, 2017      Published: March 27, 2017 ABSTRACT Enhanced chemoresistance is, among other factors, believed to be responsible for treatment failure and tumor relapse in patients with epithelial ovarian cancer (EOC). Here, we exposed EOC cells to interleukin-6 (IL-6) to activate oncogenic STAT3, which directly repressed miR-204 via a conserved STAT3-binding site near the TRPM3 promoter region upstream of miR-204. Repression of miR-204 was required for IL-6-induced cisplatin (cDDP) resistance. Furthermore, we identified the IL-6 receptor (IL-6R), which mediates IL-6-dependent STAT3 activation, as a direct miR-204 target. Importantly, the resulting IL-6R/STAT3/miR-204 feedback loop was identified in patients with EOC, and its activity correlated with chemosensitivity. Moreover, exogenous miR-204 blocked this circuit and enhanced cDDP sensitivity both in vitro and in vivo by inactivating IL-6R/STAT3 signaling and subsequently decreasing the expression of anti-apoptotic proteins. Our findings illustrate the function of this feedback loop in cDDP-based therapy and may offer a broadly useful approach to improve EOC therapy.