Zhu Xiaolan, Shen Huiling, Yin Xinming, Long Lulu, Chen Xiaofang, Feng Fan, Liu Yueqin, Zhao Peiqing, Xu Yue, Li Mei, Xu Wenlin, Li Yuefeng
Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
Jiangsu University, Medical School, Zhenjiang, Jiangsu 212003, China.
Oncotarget. 2017 Jun 13;8(24):39154-39166. doi: 10.18632/oncotarget.16610.
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.
除其他因素外，增强的化疗耐药性被认为是上皮性卵巢癌（EOC）患者治疗失败和肿瘤复发的原因。在此，我们将EOC细胞暴露于白细胞介素-6（IL-6）以激活致癌性信号转导和转录激活因子3（STAT3），STAT3通过miR-204上游TRPM3启动子区域附近的保守STAT3结合位点直接抑制miR-204。IL-6诱导的顺铂（cDDP）耐药需要miR-204的抑制。此外，我们确定介导IL-6依赖性STAT3激活的IL-6受体（IL-6R）是miR-204的直接靶点。重要的是，在EOC患者中发现了由此产生的IL-6R/STAT3/miR-204反馈回路，其活性与化疗敏感性相关。此外，外源性miR-204通过使IL-6R/STAT3信号失活并随后降低抗凋亡蛋白的表达，在体外和体内阻断了该回路并增强了cDDP敏感性。我们的研究结果阐明了该反馈回路在基于cDDP的治疗中的作用，并可能为改善EOC治疗提供一种广泛有用的方法。
