J Cancer 2020; 11(12):3446-3453. doi:10.7150/jca.41135

Research Paper

MiR-186 bidirectionally regulates cisplatin sensitivity of ovarian cancer cells via suppressing targets PIK3R3 and PTEN and upregulating APAF1 expression

Ying Xiang1,2,3✉, Ya-Jun Chen4, Yun-Bo Yan2, Yu Liu2, Jiao Qiu2, Rui-Qiao Tan2, Qing Tian1, Li Guan1, Shuai-Shuai Niu1, Hong-Wu Xin2,5✉

1. Department of Cell Biology and Genetics, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, China.
2. Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, 1 Nanhuan Road, Jingzhou, Hubei 434023, China
3. The First School of Clinical Medicine, Health Science Center, Yangtze University, Nanhuan Road, Jingzhou, Hubei 434023, China.
4. Department of Oncology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, Hubei 434023, China.
5. Department of Molecular Biology and Biochemistry, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, China.

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Citation:
Xiang Y, Chen YJ, Yan YB, Liu Y, Qiu J, Tan RQ, Tian Q, Guan L, Niu SS, Xin HW. MiR-186 bidirectionally regulates cisplatin sensitivity of ovarian cancer cells via suppressing targets PIK3R3 and PTEN and upregulating APAF1 expression. J Cancer 2020; 11(12):3446-3453. doi:10.7150/jca.41135. Available from http://www.jcancer.org/v11p3446.htm

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Abstract

Ovarian cancer is a highly lethal malignancy in the female reproductive system. Platinum drugs, represented by cisplatin, are the first-line chemotherapeutic agents for treatment of various malignancies including ovarian cancer, but drug resistance leads to chemotherapy failure. MicroRNAs emerged as promising molecules in reversal of cisplatin resistance. MiR-186 was reported to be downregulated in the cisplatin-resistant ovarian cell lines and miR-186 expression increased cisplatin sensitivity. However, we found the bidirectional regulatory effects of miR-186 on cisplatin sensitivity for the first time that overexpression of miR-186 at low concentration increased the cisplatin sensitivity of ovarian cancer cells A2780/DDP, while high concentration of miR-186 decreased the cisplatin sensitivity. The survival assay in other types of cancer cell lines verified the bidirectional regulatory function of miR-186 on cisplatin sensitivity in dose and cell type dependent manners. MiR-186 suppressed the protein levels of PTEN and PIK3R3 dose-dependently, which are opposite regulatory molecules of the oncogenic AKT pathway. MiR-186 also enhanced the protein levels of apoptotic gene APAF1 dose-dependently. We proposed the final effects of PTEN and APAF1 outweighed PIK3R3 when miR-186 at low concentration so as to increase the cisplatin sensitivity of ovarian cancer cells, while the final effects of PIK3R3 outweighed PTEN and APAF1 when miR-186 at high concentration so as to decrease the cisplatin sensitivity. We concluded the outcome of regulation of these opposite functional molecules contributed to the bidirectional regulatory effects of miR-186 in ovarian cancer cisplatin sensitivity. It deserves more attentions when developing therapeutic strategies based on the bidirectional functional miRNAs.

Keywords: ovarian cancer, miR-186, cisplatin sensitivity, dose-dependent, bidirectional regulation