Abstract
BackgroundDrug resistance is a major obstacle to successful chemotherapy for epithelial ovarian cancer (EOC). We found a subset of miRNAs associated with the response to first-line platinum-based chemotherapy in EOC by microarray, and miR-206 was one of the most significant miRNAs. The purposes of this study were to evaluate the prognostic and platinum-resistance predictive value of miR-206 in EOC patients and to investigate the functional roles of miR-206 in regulating the platinum resistance of EOC and the underlying mechanism.MethodsMiRNA expression profiling in EOC specimens was performed using a TaqMan miRNA array. miR-206 expression was confirmed by quantitative real-time PCR (qRT-PCR) analysis. Overexpression of miR-206 in EOC cell lines was achieved by the stable transfection of a recombinant plasmid. In vitro assays of cisplatin cytotoxicity, cell cycle distribution, apoptosis, transwell invasion and cell scratching were employed. Connexin 43 (Cx43) expression was detected by Western blotting. Murine xenograft models were used to determine the effects of miR-206 on platinum resistance in vivo.ResultsmiR-206 expression was increased in primary platinum-resistant EOC. High miR-206 expression was related to poor prognosis in EOC patients who received platinum-based chemotherapy and predicted chemoresistance to platinum treatment. Overexpression of miR-206 in cisplatin-sensitive EOC cell lines significantly increased cell viability, migration and invasion in the presence of cisplatin and decreased cisplatin-induced apoptosis. Cx43, a target gene of miR-206, was negatively regulated by miR-206 in EOC cell lines and significantly related to better prognosis in patients who received platinum-based chemotherapy (KmPlot). miR-206 had high expression and Cx43 had low expression in platinum-sensitive EOC cell lines compared with resistant ones. In vivo murine xenograft models showed that miR-206 profoundly promoted the chemoresistance of EOC to cisplatin treatment.ConclusionmiR-206 was highly expressed in primary platinum-resistant EOCs and functionally promoted platinum resistance in part by downregulating Cx43 expression, thereby providing a useful biomarker for prognostic and platinum-resistance prediction.
Highlights
Ovarian cancer is one of the four most common malignant tumors and the most lethal gynecologic malignancy, with an associated annual mortality rate of 152,000 [1]
Results miR‐206 was significantly increased in epithelial ovarian cancer (EOC) with incomplete response (IR), and high miR‐206 correlated with poor prognosis in EOC patients To identify the unique miRNA expression pattern associated with resistance to platinum-based chemotherapy in EOC patients, we applied miRNA microarray technology to EOC specimens from complete response (CR) and IR patients
To investigate whether miR-206 promotes cisplatin chemoresistance by targeting Connexin 43 (Cx43) in EOC, we examined the effect of miR-206 on the expression of Cx43 in EOC cell lines
Summary
Ovarian cancer is one of the four most common malignant tumors and the most lethal gynecologic malignancy, with an associated annual mortality rate of 152,000 [1]. The 5-year survival in such patients is less than 30% because of a lack of effective biomarkers for basic standard chemotherapy, prognosis, and personalized treatment [3]. Adjuvant chemotherapy drug resistance is a major cause of decreased overall survival in patients with advanced ovarian cancer. Platinumbased adjuvant chemotherapy is currently considered the standard of care for patients with advanced stage ovarian cancer following primary surgical cytoreduction, especially for serous ovarian cancer (OSC) [4]. Because of the lack of efficient biomarkers to predict chemoresistance, patients with such “platinum-resistant” tumors often receive multiple cycles of platinum-based chemotherapy without clinical benefit, lose the chance of the timely initiation of treatment with active agents, and often have a poor prognosis. Drug resistance is a major obstacle to successful chemotherapy for epithelial ovarian cancer (EOC). The purposes of this study were to evaluate the prognostic and platinum-resistance predictive value of miR-206 in EOC patients and to investigate the functional roles of miR-206 in regulating the platinum resistance of EOC and the underlying mechanism
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