Background: During cancer progression, some tumor cells show changes in their plasticity by morphological and phenotypical conversions, as an expression of mesenchymal markers and loss of epithelial markers, collectively referred to as epithelial-mesenchymal transition (EMT). EMT has been increasingly recognized as a critical phenomenon in lung cancer progression. The goal of this study was to identify microRNAs involved in lung cancer progression. Methods: A microarray and qRT-PCR were performed to investigate the miRNA expression profi les in mesenchymal lung cancer cells. The role of miR-146a in lung cancer progression was measured by invasion and migration assays in vitro. Bioinformatics and luciferase report assays were used to identify the target of miR-146a Results: The expression of miR-146a was reduced in mesenchymal phenotypes. The over-expression of miR-146a induced a marked reduction of mesenchymal marker and increase epithelial marker in several lung cancer cell lines. Moreover, the over-expression of miR- 146a suppressed lung cancer cells migration and invasion. The expression of miR-146a was down-regulated in advanced lung cancer tissues. Insulin receptor substrate 2 (IRS2) was a identifi ed target of miR-146a. IRSs are adaptor proteins that link signaling from upstream activators to multiple downstream effectors to modulate normal growth, metabolism, survival, and differentiation. miR-146a regulated the expression of IRS2 mRNA and protein level. Conclusions: These data demonstrate for the fi rst time that miR-146a was down-regulated in advanced lung cancer and suppressed lung cancer progression by repressing IRS2 expression. This sheds a new insight into the post-transcriptional regulation of lung cancer progression by miRNAs, a potential approach for the treatment of lung cancer.