MiR-770-5p inhibits cisplatin chemoresistance in human ovarian cancer by targeting ERCC2.

Henan Zhao,Jiyong Jiang,Xiaotang Yu,Chun Peng,Jinyao Zhao,Shiying Cui,Guang Wang,Gordon Zhuo Guo,Yanfang Ding,Xian Wu

doi:10.18632/oncotarget.10736

Henan Zhao, Jiyong Jiang + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.10736

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Abstract

In this study, we examined the role of the miRNA miR-770-5p in cisplatin chemotherapy resistance in ovarian cancer (OVC) patients. miR-770-5p expression was reduced in platinum-resistant patients. Using a 6.128-fold in expression as the cutoff value, miR-770-5p expression served as a prognostic biomarker and predicted the response to cisplatin treatment and survival among OVC patients. Overexpression of miR-770-5p in vitro reduced survival in chemoresistant cell lines after cisplatin treatment. ERCC2, a target gene of miR-770-5p that participates in the NER system, was negatively regulated by miR-770-5p. siRNA-mediated silencing of ERCC2 reversed the inhibition of apoptosis resulting from miR-770-5p downreglation in A2780S cells. A comet assay confirmed that this restoration of cisplatin chemosensitivity was due to the inhibition of DNA repair. These findings suggest that endogenous miR-770-5p may function as an anti-oncogene and promote chemosensitivity in OVC, at least in part by downregulating ERCC2. miR-770-5p may therefore be a useful biomarker for predicting chemosensitivity to cisplatin in OVC patients and improve the selection of effective, more personalized, treatment strategies.

Highlights

Ovarian cancer (OVC) is the leading cause of death due to gynecologic malignancies among women in developed countries
These findings suggest that endogenous miR-770-5p may function as an anti-oncogene and promote chemosensitivity in ovarian cancer (OVC), at least in part by downregulating ERCC2. miR-770-5p may be a useful biomarker for predicting chemosensitivity to cisplatin in OVC patients and improve the selection of effective, more personalized, treatment strategies
To identify miRNA expression signatures associated with resistance to chemotherapy in Epithelial ovarian cancer (EOC) patients, patient specimens were initially analyzed by miRNA microarray, the results of which were validated with Quantitative Real-Time PCR (qRT-PCR) and qualitative in situ hybridization (ISH)

Summary

Introduction

Ovarian cancer (OVC) is the leading cause of death due to gynecologic malignancies among women in developed countries. Epithelial ovarian cancer (EOC), which has a poor prognosis due to late diagnosis and high incidences of chemoresistance, accounts for approximately 90% of OVCs [1, 2]. The standard treatment protocol for the initial management of OVC is cytoreductive surgery, followed by primary chemotherapy with a platinum-based regimen [3, 4]. Chemoresistance often results in significant toxicities, such as declining bone marrow reserves, which delay the initiation of therapy with active chemo-agents and reduce quality of life [3]. Prediction of OVC patient response to platinum-based chemotherapy and identification of the most effective agent based on primary tumor gene expression data may assist in optimizing the selection of personalized treatment regimens

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