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.
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.
authors.affiliation: Corresponding Author: Masahiro Seike, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. mseike@nms.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kitamura
authors.forename: Masahiro
authors.initials: M
authors.lastname: Seike
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Okano
authors.forename: Kuniko
authors.initials: K
authors.lastname: Matsuda
authors.forename: Akihiko
authors.initials: A
authors.lastname: Miyanaga
authors.forename: Hideaki
authors.initials: H
authors.lastname: Mizutani
authors.forename: Rintaro
authors.initials: R
authors.lastname: Noro
authors.forename: Yuji
authors.initials: Y
authors.lastname: Minegishi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kubota
authors.forename: Akihiko
authors.initials: A
authors.lastname: Gemma
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077156:Gefitinib; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D051528:Guanylate Kinases; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C569273:MIRN134 microRNA, human; C568526:MIRN487 microRNA, human; C585264:MIRN655 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D053773:Transforming Growth Factor beta1; D066246:ErbB Receptors; D051528:Guanylate Kinases; C485777:MAGI2 protein, human; C446603:TPTE protein, human; D051059:PTEN Phosphohydrolase; D000077156:Gefitinib