期刊
ONCOTARGET
卷 8, 期 24, 页码 39154-39166出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.16610
关键词
miR-204; IL-6R; STAT3; chemoresistance; EOC
资金
- Natural Science Foundation of China [81402165/81301194/81672913]
- Six talent peaks project in Jiangsu Province [2016-WSW-125]
- 333 Project research projects in Jiangsu Province [BRA2016141]
- Natural Science Foundation of Jiangsu Province [BK20141288]
- Maternal and Child Health Research Projects of Jiangsu Province [F201437]
- Jiangsu Provincial Medical Youth Talent [QNRC2016460]
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.
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