RRC ID 68848
Author Kitamura K, Seike M, Okano T, Matsuda K, Miyanaga A, Mizutani H, Noro R, Minegishi Y, Kubota K, Gemma A.
Title MiR-134/487b/655 cluster regulates TGF-β-induced epithelial-mesenchymal transition and drug resistance to gefitinib by targeting MAGI2 in lung adenocarcinoma cells.
Journal Mol Cancer Ther
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.
Volume 13(2)
Pages 444-53
Published 2014-2-1
DOI 10.1158/1535-7163.MCT-13-0448
PII 1535-7163.MCT-13-0448
PMID 24258346
MeSH Adaptor Proteins, Signal Transducing Adenocarcinoma / genetics Adenocarcinoma / metabolism Adenocarcinoma / pathology Blotting, Western Carcinoma, Non-Small-Cell Lung / genetics Carcinoma, Non-Small-Cell Lung / metabolism Carcinoma, Non-Small-Cell Lung / pathology Carrier Proteins / genetics* Carrier Proteins / metabolism Cell Line, Tumor Drug Resistance, Neoplasm / genetics Epithelial-Mesenchymal Transition / drug effects* Epithelial-Mesenchymal Transition / genetics ErbB Receptors / antagonists & inhibitors ErbB Receptors / metabolism Gefitinib Gene Expression Profiling Gene Expression Regulation, Neoplastic Guanylate Kinases Humans Lung Neoplasms / genetics Lung Neoplasms / metabolism Lung Neoplasms / pathology Membrane Proteins / metabolism MicroRNAs / genetics* Oligonucleotide Array Sequence Analysis PTEN Phosphohydrolase / metabolism Protein Kinase Inhibitors / pharmacology Quinazolines / pharmacology Reverse Transcriptase Polymerase Chain Reaction Transforming Growth Factor beta1 / pharmacology*
IF 5.615
Human and Animal Cells A549(RCB0098) LC-2/ad(RCB0440) RERF-LC-KJ(RCB1313)