Methylation-associated Has-miR-9 deregulation in paclitaxel- resistant epithelial ovarian carcinoma.

Xiao Li,Xing Xie,Xiaodong Cheng,Yuyan Mao,Qianqian Pan,Xiaoyun Wan,Weiguo Lu

doi:10.1186/s12885-015-1509-1

Abstract

BackgroundDrug resistance is still one of the key causes of death in epithelial ovarian carcinoma (EOC) patients, however there are very few strategies to reverse chemoresistance. Here we try to clarify whether and how miR-9 takes part in the regulation of paclitaxel sensitivity.MethodsmiR-9 expressions in EOC cells and tissues were detected by Realtime PCR. The target of miR-9 was validated through dual luciferase reporter assay and Western Blot. Methylation study, RNAi technique and cytotoxicity assay were used to determine the intrinsic mechanism of miR-9 in paclitaxel sensitivity regulation.ResultsmiR-9 is down-regulated in paclitaxel resistant EOC. The patients with lower miR-9, Grade 3, Stage III –IV and suboptimal surgery present shorter survival time. miR-9 and suboptimal surgery are independent prognostic factors of EOC. Modulating miR-9 expression could change paclitaxel sensitivity of EOC cells. CCNG1, validated as a direct target of miR-9, mediates paclitaxel resistance. miR-9-1 and 3 gene hypermethylation would decrease miR-9 expression, while demethylation of miR-9 gene could restore miR-9 expression and improve paclitaxel sensitivity in chemoresistance EOC cells. Furthermore, methylation-associated miR-9 deregulation in EOC cells could be induced by paclitaxel exposure.ConclusionsMethylation-associated miR-9 down-regulation is probably one of the key mechanisms for paclitaxel resistance in EOC cells, via targeting CCNG1. Our findings may also provide a new potential therapeutic target to reverse paclitaxel resistance in EOC patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1509-1) contains supplementary material, which is available to authorized users.

Highlights

Drug resistance is still one of the key causes of death in epithelial ovarian carcinoma (EOC) patients, there are very few strategies to reverse chemoresistance
Results miR-9 expression is down-regulated in paclitaxel resistant EOCs and correlated with prognosis In accordance with our previous results [13], we validated that miR-9 expressions were reduced by 95.26-fold and 18.96-fold in paclitaxel resistant ST30 and A2780R cell lines, compared with their parental cell lines respectively (Fig. 1a)
Further detection revealed that miR-9 expressions in 22 chemoresistant EOC patients were reduced by 7.80-fold compared with 44 chemosensitive EOC patients (Fig. 1b), which was consistent with our previous result of formalin-fixed paraffin-embedded samples [13]

Summary

Introduction

Drug resistance is still one of the key causes of death in epithelial ovarian carcinoma (EOC) patients, there are very few strategies to reverse chemoresistance. Improved combination of surgery and chemotherapy is commonly applied for epithelial ovarian carcinoma (EOC), EOC is still the leading cause of death among gynecologic cancer nowadays [1, 2]. Initial response to chemotherapeutic drugs can be achieved in about 70 % EOC patients, but most of patients eventually develop chemoresistance and succumb to their diseases [1, 3]. Numerous evidences showed that chemoresistance is a clinically formidable problem in managing EOC patients. Reversion of drug resistance would contribute to improve prognosis. As we know,miRNAs are small noncoding RNAs involved in the initiation and progression of human cancer [4].

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Conclusion