MicroRNA-223-3p regulates cell chemo-sensitivity by targeting FOXO3 in prostatic cancer

Abstract

Prostate cancer (PCa) is one of the most common malignant cancers in male and docetaxel is commonly used as an effective chemotherapeutic drug for PCa patients. However, docetaxel resistance inhibits the therapeutic effect of this agent, thus investigating the mechanism of chemoresistance to docetaxel of PCa may help to improve the prognosis of PCa patients. In our present study, we found that miR-223-3p was up-regulated in PCa cell lines (C4-2, LNCap, PC3, DU-145). Transfection with miR-223-3p inhibitor increased chemo-sensitivity to docetaxel and cell apoptosis rate in PCa cells compared with docetaxel + miR-223-3p mock group, especially in DU-145 cells which were more resistant to docetaxel. Bioinformatics study and luciferase reporter assay indicated that FOXO3 was a target of miR-223-3p and the results from western blot suggested that FOXO3 was negatively regulated by miR-223-3p. Further study revealed that up-regulation of FOXO3 by transfection with pCMV-FOXO3 decreased the IC50 values of docetaxel and increased cell apoptosis rate compared with docetaxel + pCMV-vector group, suggesting that overexpressed FOXO3 suppressed cell survival and sensitized PCa cells to docetaxel. Moreover, siRNA-mediated knockdown of FOXO3 abolished the effects of miR-223-3p inhibitor on chemo-sensitivity and apoptosis in PCa cells by increasing chemoresistance and decreasing cell apoptosis rate. Finally, the in vivo experiments showed that miR-223-3p inhibitor sensitized prostatic cancer mouse model to docetaxel by increasing the expression of FOXO3. In conclusion, our present study indicated that miR-223-3p regulated cell chemo-sensitivity by targeting FOXO3 in prostatic cancer both in vitro and in vivo, providing new potential therapeutic strategy for PCa treatment.