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

Xiaolan Zhu,Mei Li,Xinming Yin,Yuefeng Li,Fan Feng,Lulu Long,Xiaofang Chen,Wenlin Xu,Huiling Shen,Yue Xu,Peiqing Zhao,Yueqin Liu

doi:10.18632/oncotarget.16610

Xiaolan Zhu, Mei Li + Show 10 more

Open Access

https://doi.org/10.18632/oncotarget.16610

Copy DOI

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.

Highlights

Patients with epithelial ovarian cancer (EOC) typically present with advanced disease often relapse, even with optimal debulking and response to adjuvant chemotherapy
Recombinant IL-6 phosphorylated signal transducer and activator of transcription 3 (STAT3), an effector of IL-6 signaling, presumably activating STAT3 in EOC cells (Figure 1F), which is typical for IL-6-mediated STAT3 activation
Despite impressive initial clinical responses, the majority of EOC patients eventually develop some degree of resistance to cDDP-based therapy, which results in a high relapse rate

Summary

Introduction

Patients with epithelial ovarian cancer (EOC) typically present with advanced disease often relapse, even with optimal debulking and response to adjuvant chemotherapy. Interleukin-6 (IL-6), a proinflammatory cytokine produced by several types of immune cells and carcinomas, is an important mediator of the tumor-promoting effects of inflammation, especially in later states of tumorigenesis [9, 10]. In addition www.impactjournals.com/oncotarget to its local effects in the tumor microenvironment, tumorderived IL-6 can stimulate paraneoplastic thrombocytosis in patients with advanced EOC, which is associated with poor prognosis [11, 12]. These findings indicate the therapeutic potential of targeting IL-6 and its downstream signaling

Methods

Results

Conclusion