The role of miR-125b-mitochondria-caspase-3 pathway in doxorubicin resistance and therapy in human breast cancer.

MicroRNAs (miRNAs) are a class of naturally occurring, small, non-coding RNAs which play important roles in diverse biological processes and are acting as key regulators of tumorigenesis and chemotherapy resistance. In this study, a downregulation of miR-125b was observed in breast cancer cell lines, suggesting miR-125b is a tumor suppressor in breast cancer. Moreover, the miR-125b levels were significantly decreased in doxorubicin-resistant MCF-7 (MCF-7/DR) cells compared with MCF-7 cells. Transfection of miR-125b significantly enhanced the cytotoxicity of doxorubicin to MCF-7/DR cells. However, the overexpression of miR-125b did not influence the doxorubicin accumulation but downregulated the myeloid cell leukemia-1 (Mcl-1) levels, which may be the mechanism of apoptosis induction caused by doxorubicin combining with miR-125b in MCF-7/DR cells. Furthermore, luciferase reporter assay proved that Mcl-1 is the target of miR-125b. Importantly, we found that the sensitization of miR-125b to doxorubicin cytotoxicity is caspase-dependent in MCF-7/DR cells, which can be inhibited by zVAD-fmk. Finally, we indicated that the treatment of miR-125b plus doxorubicin leads to loss of mitochondrial membrane potential (MMP) and mitochondria outer membrane permeability (MOMP), which were interacted with the activation of caspases. Thus, this study revealed the role of miR-125b in doxorubicin resistance and therapy, which may provide novel approaches for the treatment of breast cancer.