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.