title: 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.
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, P.R. China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Tianjin Children's Hospital, Tianjin 300074, P.R. China.
authors.forename: Nan
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, P.R. China.
authors.forename: Yintao
authors.initials: Y
authors.lastname: Ye
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, P.R. China.
authors.forename: Junqiang
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Clinical Laboratory, Tianjin Huan Hu Hospital, Tianjin Key Laboratory of Cerebral Vessels and Neural Degeneration, Tianjin 300060, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, P.R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004720:Endonucleases / Q000235:genetics; D016193:G1 Phase / Q000235:genetics; D005978:Glutathione / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D016328:NF-kappa B / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D016192:Resting Phase, Cell Cycle / Q000235:genetics; D020112:Rhodamine 123 / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D004720:Endonucleases; D005978:Glutathione; D015850:Interleukin-6; D016209:Interleukin-8; D035683:MicroRNAs; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D016328:NF-kappa B; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D020112:Rhodamine 123; D013482:Superoxide Dismutase; C508600:IL6 protein, human; C071447:ERCC1 protein, human; C421109:multidrug resistance-associated protein 1