Oncotarget

Research Papers:

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

Qing-yong Chen _, De-min Jiao, Jian Wang, Huizhen Hu, Xiali Tang, Jun Chen, Hao Mou and Wei Lu

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Oncotarget. 2016; 7:24510-24526. https://doi.org/10.18632/oncotarget.8229

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Abstract

Qing-yong Chen1,*, De-min Jiao1,*, Jian Wang1,*, Huizhen Hu1,*, Xiali Tang1, Jun Chen1, Hao Mou1, Wei Lu2

1Department of Respiratory Disease, The 117th Hospital of PLA, Hangzhou, Zhejiang, 310013, P.R. China

2Department 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.


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