MicroRNA-101 sensitizes hepatocellular carcinoma cells to doxorubicin-induced apoptosis via targeting Mcl-1.

Abstract

MicroRNAs (miRNAs/miRs) are important regulators of multiple cellular processes, and their dysregulation is a common event in tumorigenesis, including the development of hepatocellular carcinoma (HCC). Studies have shown that certain miRNAs are associated with resistance to chemotherapy or drug sensitization; however, the underlying mechanisms have largely remained elusive. Multiple drug resistance is a major barrier for the treatment of advanced HCC. In the present study, miR-101 was observed to be downregulated in a panel of HCC cell lines, suggesting that it has a tumor suppressor role. Furthermore, transfection of miR-101 significantly enhanced the cytotoxicity of doxorubicin to HepG2 cells. While overexpression of miR-101 did not influence the accumulation of doxorubicin, it promoted the apoptosis-inducing effect of doxorubicin in HepG2 cells. A bioinformatics analysis predicted that miR-101 directly targeted the 3'-untranslated region of myeloid cell leukemia 1 (Mcl-1), which was verified by a luciferase reporter assay. Finally, transfection of HepG2 cells with Mcl-1 expression plasmid inhibited apoptosis caused by doxorubicin plus miR-101 expression. In conclusion, the present study showed that miR-101 is a negative regulator of Mcl-1 in HCC, and the combination of miR-101 expression with doxorubicin may represent a novel approach for the treatment of HCC.