title: IL-6R/STAT3/miR-204 feedback loop contributes to cisplatin resistance of epithelial ovarian cancer cells.
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.
authors.affiliation: Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.|Jiangsu University, Medical School, Zhenjiang, Jiangsu 212003, China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Jiangsu University, Medical School, Zhenjiang, Jiangsu 212003, China.|Department of Oncology, The Affiliated People Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
authors.forename: Huiling
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
authors.forename: Xinming
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Oncology, The Affiliated People Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Long
authors.affiliation: Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Feng
authors.affiliation: Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
authors.forename: Yueqin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Jiangsu University, Medical School, Zhenjiang, Jiangsu 212003, China.
authors.forename: Peiqing
authors.initials: P
authors.lastname: Zhao
authors.affiliation: Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Gynecologic Oncology, The Fourth Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Radiology, The Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu 212001, China.
authors.forename: Yuefeng
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D025461:Feedback, Physiological; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D015850:Interleukin-6; C549404:MIRN204 microRNA, human; D035683:MicroRNAs; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D002945:Cisplatin
keywords: EOC; IL-6R; STAT3; chemoresistance; miR-204