miR-206 regulates cisplatin resistance and EMT in human lung adenocarcinoma cells partly by targeting MET

// Qing-yong Chen 1, * , De-min Jiao 1, * , Jian Wang 1, * , Huizhen Hu 1, * , Xiali Tang 1 , Jun Chen 1 , Hao Mou 1 , Wei Lu 2 1 Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang, 310013, P.R. China 2 Department of Oncology, The 117th Hospital of PLA, Hangzhou, Zhejiang, 310013, P.R. China * These authors have contributed equally to this work Correspondence to: Qingyong Chen, e-mail: cqyong117@163.com Wei Lu, e-mail: luwei3603@163.com Keywords: miR-206, cisplatin resistance, epithelial-mesenchymal transition (EMT), MET, lung adenocarcinoma Received: April 27, 2015      Accepted: March 04, 2016      Published: March 21, 2016 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.