MiR-134/487b/655 Cluster Regulates TGF-β–Induced Epithelial–Mesenchymal Transition and Drug Resistance to Gefitinib by Targeting <i>MAGI2</i> in Lung Adenocarcinoma Cells

Abstract

Epithelial-mesenchymal transition (EMT) has recently been recognized as a key element of cell invasion, migration, metastasis, and drug resistance in several types of cancer, including non-small cell lung cancer (NSCLC). Our aim was to clarify microRNA (miRNA)-related mechanisms underlying EMT followed by acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in NSCLC. miRNA expression profiles were examined before and after transforming growth factor β1 (TGF-β1) exposure in four human adenocarcinoma cell lines with or without EMT. Correlation between expressions of EMT-related miRNAs and resistance to EGFR-TKI gefitinib was evaluated. miRNA array and real-time quantitative reverse transcription PCR (qRT-PCR) revealed that TGF-β1 significantly induced overexpression of miR-134, miR-487b, and miR-655, which belong to the same cluster located on chromosome 14q32, in lung adenocarcinoma cells with EMT. MAGI2 (membrane-associated guanylate kinase, WW, and PDZ domain-containing protein 2), a predicted target of these miRNAs and a scaffold protein required for PTEN, was diminished in A549 cells with EMT after the TGF-β1 stimulation. Overexpression of miR-134 and miR-487b promoted the EMT phenomenon and affected the drug resistance to gefitinib, whereas knockdown of these miRNAs inhibited the EMT process and reversed TGF-β1-induced resistance to gefitinib. Our study demonstrated that the miR-134/487b/655 cluster contributed to the TGF-β1-induced EMT phenomenon and affected the resistance to gefitinib by directly targeting MAGI2, in which suppression subsequently caused loss of PTEN stability in lung cancer cells. The miR-134/miR-487b/miR-655 cluster may be a new therapeutic target in patients with advanced lung adenocarcinoma, depending on the EMT phenomenon.