title: miR-206 regulates cisplatin resistance and EMT in human lung adenocarcinoma cells partly by targeting MET.
abstract: MicroRNAs (miRNAs) play a critical role in drug resistance and epithelial-mesenchymal transition (EMT). The aims of this study were to explore the potential role of miR-206 in governing cisplatin resistance and EMT in lung cancer cells. We found that both lung adenocarcinoma A549 cisplatin-resistant cells (A549/DDP) and H1299 cisplatin-resistant cells (H1299/DDP) acquired mesenchymal features and were along with low expression of miR-206 and high migration and invasion abilities. Ectopic expression of miR-206 mimics inhibited cisplatin resistance, reversed the EMT phenotype, decreased the migration and invasion in these DDP-resistant cells. In contrast, miR-206 inhibitors increased cisplatin resistance, EMT, cell migration and invasion in non-DDP-resistant cells. Furthermore, we found that MET is the direct target of miR-206 in lung cancer cells. Knockdown of MET exhibited an EMT and DDP resistant inhibitory effect on DDP-resistant cells. Conversely, overexpression of MET in non-DDP- resistant cells produced a promoting effect on cell EMT and DDP resistance. In lung adenocarcinoma tissues, we demonstrated that low expression of miR-206 were also correlated with increased cisplatin resistance and MET expression. In addition, we revealed that miR-206 overexpression reduced cisplatin resistance and EMT in DDP-resistant cells, partly due to inactivation of MET/PI3K/AKT/mTOR signaling pathway, and subsequent downregulation of MDR1, ZEB1 and Snail expression. Finally, we found that miR-206 could also sensitize A549/DDP cells to cisplatin in mice model. Taken together, our study implied that activation of miR-206 or inactivation of its target gene pathway could serve as a novel approach to reverse cisplatin resistance in lung adenocarcinomas cells.
authors.affiliation: Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang, 310013, P.R. China.
authors.forename: Qing-Yong
authors.initials: QY
authors.lastname: Chen
authors.affiliation: Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang, 310013, P.R. China.
authors.forename: De-Min
authors.initials: DM
authors.lastname: Jiao
authors.affiliation: Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang, 310013, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang, 310013, P.R. China.
authors.forename: Huizhen
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang, 310013, P.R. China.
authors.forename: Xiali
authors.initials: X
authors.lastname: Tang
authors.affiliation: Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang, 310013, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang, 310013, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Mou
authors.affiliation: Department of Oncology, The 117th Hospital of PLA, Hangzhou, Zhejiang, 310013, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
mesh_terms: D000072283:A549 Cells; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C546087:MIRN206 microRNA, human; D035683:MicroRNAs; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D002945:Cisplatin
keywords: MET; cisplatin resistance; epithelial-mesenchymal transition (EMT); lung adenocarcinoma; miR-206