title: Downregulation of miR-363 increases drug resistance in cisplatin-treated HepG2 by dysregulating Mcl-1.
abstract: Systemic therapy with cytotoxic agents provides marginal benefit in hepatocellular carcinoma (HCC) treatment especially for patients with advanced HCC. Cisplatin is one of the most active cytotoxic agents for HCC treatment. However, acquisition of cisplatin resistance is common, and one important underlying mechanism of such resistance is apoptosis-resistance. In this study, we found that miR-363 levels were significantly decreased in HCC patients treated with cisplatin-based chemotherapy. MiR-363 levels were also lower in cisplatin-resistant HepG2 (HepG2-R) cells than in HepG2 cells. Exogenous miR-363 significantly overcame cisplatin resistance in HepG2-R cells, whereas miR-363 knockdown increased the cell viability during cisplatin treatment. We further demonstrated that miR-363 directly targeted to Mcl-1 3'-UTR (3'-Untranslated Regions). Downregulation of miR-363 resulted in upregulation of Mcl-1 which is a key member of anti-apoptotic Bcl-2 family and increased drug resistance. We finally demonstrated that miR-363 decreased cisplatin resistance of HCC cell, partly by targeting Mcl-1. These data suggest that the combination of miR-363 and cisplatin may represent a novel approach in treatment for HCC, thus offering a new target for chemotherapy of HCC.
authors.affiliation: Xiangya Hospital of Central-South University, Changsha, Hunan 410008, PR China.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Ou
authors.affiliation: Xiangya Hospital of Central-South University, Changsha, Hunan 410008, PR China.
authors.forename: Denggao
authors.initials: D
authors.lastname: Zhai
authors.affiliation: Xiangya Hospital of Central-South University, Changsha, Hunan 410008, PR China.
authors.forename: Nan
authors.initials: N
authors.lastname: Wu
authors.affiliation: Xiangya Hospital of Central-South University, Changsha, Hunan 410008, PR China. Electronic address: changshaxiaolili@163.com.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics*; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D020413:3' Untranslated Regions; D000970:Antineoplastic Agents; C579095:MCL1 protein, human; C574861:MIRN363 microRNA, human; D035683:MicroRNAs; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D002945:Cisplatin
keywords: Apoptosis; Cisplatin; HepG2-R; Mcl-1; MiR-363