title: EGFR and MET receptor tyrosine kinase-altered microRNA expression induces tumorigenesis and gefitinib resistance in lung cancers.
abstract: The involvement of the MET oncogene in de novo and acquired resistance of non-small cell lung cancers (NSCLCs) to tyrosine kinase inhibitors (TKIs) has previously been reported, but the precise mechanism by which MET overexpression contributes to TKI-resistant NSCLC remains unclear. MicroRNAs (miRNAs) negatively regulate gene expression, and their dysregulation has been implicated in tumorigenesis. To understand their role in TKI-resistant NSCLCs, we examined changes in miRNA that are mediated by tyrosine kinase receptors. Here we report that miR-30b, miR-30c, miR-221 and miR-222 are modulated by both epidermal growth factor (EGF) and MET receptors, whereas miR-103 and miR-203 are controlled only by MET. We showed that these miRNAs have important roles in gefitinib-induced apoptosis and epithelial-mesenchymal transition of NSCLC cells in vitro and in vivo by inhibiting the expression of the genes encoding BCL2-like 11 (BIM), apoptotic peptidase activating factor 1 (APAF-1), protein kinase C ɛ (PKC-ɛ) and sarcoma viral oncogene homolog (SRC). These findings suggest that modulation of specific miRNAs may provide a therapeutic approach for the treatment of NSCLCs.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, Ohio State University, Columbus, Ohio, USA.
authors.forename: Michela
authors.initials: M
authors.lastname: Garofalo
authors.forename: Giulia
authors.initials: G
authors.lastname: Romano
authors.forename: Gianpiero
authors.initials: G
authors.lastname: Di Leva
authors.forename: Gerard
authors.initials: G
authors.lastname: Nuovo
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Jeon
authors.forename: Apollinaire
authors.initials: A
authors.lastname: Ngankeu
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Gerolama
authors.initials: G
authors.lastname: Condorelli
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Mayumi
authors.initials: M
authors.lastname: Ono
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Rho
authors.forename: Luciano
authors.initials: L
authors.lastname: Cascione
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Nephew
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics*; D011799:Quinazolines / Q000627:therapeutic use*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; D011799:Quinazolines; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D000077156:Gefitinib