Targeting of SGK1 by miR-576-3p Inhibits Lung Adenocarcinoma Migration and Invasion.

Metastatic lung cancer is common in patients with lung adenocarcinoma, but the molecular mechanisms of metastasis remain incompletely resolved. miRNA regulate gene expression and contribute to cancer development and progression. This report identifies miR-576-3p and its mechanism of action in lung cancer progression. miR-576-3p was determined to be significantly decreased in clinical specimens of late-stage lung adenocarcinoma. Overexpression of miR-576-3p in lung adenocarcinoma cells decreased mesenchymal marker expression and inhibited migration and invasion. Inhibition of miR-576-3p in nonmalignant lung epithelial cells increased migration and invasion as well as mesenchymal markers. Serum/glucocorticoid-regulated kinase 1 (SGK1) was a direct target of miR-576-3p, and modulation of miR-576-3p levels led to alterations in SGK1 protein and mRNA as well as changes in activation of its downstream target linked to metastasis, N-myc downstream regulated 1 (NDRG1). Loss of the ability of miR-576-3p to bind the 3'-UTR of SGK1 rescued the inhibition in migration and invasion observed with miR-576-3p overexpression. In addition, increased SGK1 levels were detected in lung adenocarcinoma patient samples expressing mesenchymal markers, and pharmacologic inhibition of SGK1 resulted in a similar inhibition of migration and invasion of lung adenocarcinoma cells as observed with miR-576-3p overexpression. Together, these results reveal miR-576-3p downregulation is selected for in late-stage lung adenocarcinoma due to its ability to inhibit migration and invasion by targeting SGK1. Furthermore, these results also support targeting SGK1 as a potential therapeutic for lung adenocarcinoma. IMPLICATIONS: This study reveals SGK1 inhibition with miR-576-3p or pharmacologically inhibits migration and invasion of lung adenocarcinoma, providing mechanistic insights into late-stage lung adenocarcinoma and a potential new treatment avenue. ©2018 American Association for Cancer Research.