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.
Keywords:
EOC; IL-6R; STAT3; chemoresistance; miR-204.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Carcinoma, Ovarian Epithelial
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Cell Proliferation / drug effects
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Cisplatin / pharmacology*
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Cystadenocarcinoma, Serous / drug therapy
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Cystadenocarcinoma, Serous / genetics
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Cystadenocarcinoma, Serous / metabolism
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Cystadenocarcinoma, Serous / pathology
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Drug Resistance, Neoplasm*
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Feedback, Physiological*
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Female
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Follow-Up Studies
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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MicroRNAs / genetics*
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Neoplasms, Glandular and Epithelial / drug therapy
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Neoplasms, Glandular and Epithelial / genetics
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Neoplasms, Glandular and Epithelial / metabolism
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Neoplasms, Glandular and Epithelial / pathology*
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Ovarian Neoplasms / drug therapy
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology*
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Prognosis
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Receptors, Interleukin-6 / genetics
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Receptors, Interleukin-6 / metabolism*
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism*
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Signal Transduction / drug effects
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Survival Rate
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Tumor Cells, Cultured
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Biomarkers, Tumor
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Interleukin-6
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MIRN204 microRNA, human
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MicroRNAs
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Receptors, Interleukin-6
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STAT3 Transcription Factor
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STAT3 protein, human
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Cisplatin