title: MicroRNA-451 induces epithelial-mesenchymal transition in docetaxel-resistant lung adenocarcinoma cells by targeting proto-oncogene c-Myc.
abstract: Epithelial-mesenchymal transition (EMT) has been reported to play a significant role in tumour metastasis as well as chemoresistance. However, the molecular mechanisms involved in chemotherapy-induced EMT are still unclear. MicroRNA (miRNA) expression and functions have been reported to contribute to phenotypic features of tumour cells. To investigate the roles of miRNAs in chemotherapy-induced EMT, we established two docetaxel-resistant lung adenocarcinoma (LAD) cell models (SPC-A1/DTX and H1299/DTX), which display EMT-like properties and gain increased invasion or migration activity. MiR-451 was found to be significantly downregulated in docetaxel-resistant LAD cells, and re-expression of miR-451 could reverse EMT to mesenchymal-epithelial transition (MET) and inhibit invasion and metastasis of docetaxel-resistant LAD cells both in vitro and in vivo. The proto-oncogene c-Myc was identified as a direct and functional target of miR-451, and further researches confirmed that overexpression of c-Myc which induced extracellular-signal-regulated kinase (ERK)-dependent glycogen synthase kinase-3 beta (GSK-3β) inactivation and subsequent snail activation is essential for acquisition of EMT phenotype induced by loss of miR-451. Furthermore, c-Myc was significantly upregulated in docetaxel-non-responding LAD tissues in comparison with docetaxel-responding tissues, and its expression was inversely correlated with miR-451 expression. This study first reported the involvement of miR-451/c-Myc/ERK/GSK-3β signalling axis in the acquisition of EMT phenotype in docetaxel-resistant LAD cells, suggesting that re-expression of miR-451 or targeting c-Myc will be a potential strategy for the treatment of chemoresistant LAD patients.
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Dongqin
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Jiayuan
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Banzhou
authors.initials: B
authors.lastname: Pan
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu 210002, China.
authors.forename: Wei
authors.initials: W
authors.lastname: De
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China. Electronic address: wangrui218@163.com.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu 210002, China. Electronic address: chenlongbang@yeah.net.
authors.forename: Longbang
authors.initials: L
authors.lastname: Chen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects* / Q000235:genetics; D043823:Taxoids / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; C531201:MIRN451 microRNA, human; D035683:MicroRNAs; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D043823:Taxoids; D000077143:Docetaxel
keywords: Chemoresistance; Epithelial–mesenchymal transition; Invasion; Lung adenocarcinoma; Metastasis; c-Myc; miR-451