MicroRNA-16 sensitizes drug-resistant breast cancer cells to Adriamycin by targeting Wip1 and Bcl-2

摘要

Clinical evidence indicates that drug resistance is a major obstacle in the treatment of breast cancer (BC). Drug resistance results in the disease being uncontrollable, and leads to high mortality rates. The aim of the present study was to investigate the chemosensitizing effect of microRNA (miR)-16 on Adriamycin (ADM)-resistant BC cells and the associated mechanisms. BC tumors from 40 patients were collected and reverse transcription-quantitative PCR was used to examine the expression of miR-16. ADM-sensitive (MCF-7/S) and -resistant (MCF-7/A) BC cell lines were used to determine the expression of miR-16 prior to and following transfection with miR-16 mimics or inhibitor. The effects of increased and decreased miR-16 expression on the chemosensitivity of BC cells to ADM was analyzed using MTT, colony survival and flow cytometry assays. miR-16 was found to regulate wild-type p53-induced phosphatase 1 (Wip1) and Bcl-2 expression, as confirmed by western blotting, immunofluorescence staining and luciferase reporter assays. miR-16 expression in drug-resistant tumor tissues and cells was decreased, compared with that the drug-sensitive equivalents. Overexpression of miR-16 in MCF-7/A was associated with a sharp downregulation of Wip1 and Bcl-2 expression, leading to increased ADM-induced cell apoptosis and sensitization of MCF-7/A cells to ADM treatment. Taken together, the results demonstrate that miR-16 may serve as an effective chemosensitizing target to enhance the effects of chemotherapy in drug-resistant BC cells with high Wip1 and Bcl-2 expression. This provides a novel approach to improving the chemotherapeutic efficacy in drug-resistant BC via regulation of miRs.