Role and mechanisms of microRNA‑503 in drug resistance reversal in HepG2/ADM human hepatocellular carcinoma cells.

Abstract

Hepatocellular carcinoma is one of the most common malignancies worldwide and drug resistance is a major cause of treatment failure. In order to investigate the effects and mechanisms of microRNA‑503 (miR‑503) in the reversal of Adriamycin® (ADM) resistance in the drug‑resistant HepG2/ADM hepatocellular cancer cell line, an ADM‑resistant HepG2/ADM cell line was established using continuous drug exposure. HepG2/ADM cells overexpressing miR‑503 were further established. HepG2/ADM cells overexpressing miR‑503 demonstrated an enhanced sensitivity to ADM. Furthermore, miR‑503 overexpression was found to increase intracellular rhodamine‑123 levels and the rate of apoptosis, block the cell cycle at G0/G1‑phase and significantly decrease intracellular superoxide dismutase and glutathione levels. The expression of a number drug resistance‑related proteins, including multidrug resistance 1, multi drug resistance‑associated protein 1, DNA excision repair protein ERCC‑1, survivin and B‑cell lymphoma 2, was significantly downregulated by miR‑503 overexpression, as indicated by western blotting and a quantitative polymerase chain reaction. By contrast, levels of RhoE were increased. In addition, the phosphorylation of Akt was decreased and expression of cyclin‑dependent kinase 1 was decreased by miR‑503 overexpression. Furthermore, the secretion of transforming growth factor‑β, interleukin (IL)‑6 and IL‑8 was downregulated, and the transcriptional activities of nuclear factor κ‑light‑chain‑enhancer of activated B cells and activating protein‑1 were significantly reduced. In conclusion, miR‑503 was observed to reverse ADM resistance in HepG2/ADM cells by inhibiting drug efflux, downregulating the expression of drug resistance‑related proteins, blocking the cell cycle and promoting cell apoptosis.