MiR-497 decreases cisplatin resistance in ovarian cancer cells by targeting mTOR/P70S6K1.

Shaohua Xu,Xiaoping Wan,Ke Chen,Bing-Hua Jiang,Guang-Bo Fu,Jun Ouyang,Zhen Tao,Fanfei Kong

doi:10.18632/oncotarget.4762

Abstract

The mechanism of cisplatin resistance in ovarian cancer is not clearly understood. In the present investigation, we found that the expression levels of miR-497 were reduced in chemotherapy-resistant ovarian cancer cells and tumor tissues due to hypermethylation of miR-497 promoter. Low miR-497 expression levels were associated with chemo-resistant phonotype of ovarian cancer. By analyzing the expression levels of miR-497, mTOR and p70S6K1 in a clinical gene-expression array dataset, we found that mTOR and p70S6K1, two proteins correlated to chemotherapy-resistance in multiple types of human cancers, were inversely correlated with miR-497 levels in ovarian cancer tissues. By using an orthotopic ovarian tumor model and a Tet-On inducible miR-497 expression system, our results demonstrated that overexpression of miR-497 sensitizes the resistant ovarian tumor to cisplatin treatment. Therefore, we suggest that miR-497 might be used as a therapeutic supplement to increase ovarian cancer treatment response to cisplatin.

Highlights

Epithelial ovarian carcinoma is the leading cause of death worldwide from gynecological malignancies [1]
To determine the crucial miRNAs involved in ovarian cancer cisplatin resistance, we performed microarray assay to profile the global expression of mature miRNAs in A2780 and A2780/CP cell lines
The results showed that miR-497 levels were significantly reduced in SKOV3/ CP cells compared with SKOV3 cells (Figure 1F)

Summary

Introduction

Epithelial ovarian carcinoma is the leading cause of death worldwide from gynecological malignancies [1]. The overall prognosis remains disappointing [2, 3]. More than 75% of patients diagnosed with epithelial ovarian carcinoma are at advanced-staged, and the 5-year survival rate is less than 30% [4]. Cisplatin is one of the most effective and commonly used chemotherapeutics agents for the treatment of ovarian cancer. The development of cisplatin-based resistance limits its successful clinical application in cancer patients [5]. Despite the knowledge that has been accumulated over decades, the mechanisms of cisplatin resistance are not fully understood

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Conclusion