title: MicroRNA-21, up-regulated by arsenite, directs the epithelial-mesenchymal transition and enhances the invasive potential of transformed human bronchial epithelial cells by targeting PDCD4.
abstract: Arsenic is well established as a human carcinogen, but the molecular mechanisms leading to arsenic-induced carcinogenesis are complex and elusive. It is not been determined if the epithelial-mesenchymal transition (EMT) contributes to carcinogen-induced malignant transformation and subsequent tumor formation. We have found that, during the neoplastic transformation induced in human bronchial epithelial (HBE) cells by a low concentration (1.0μM) of arsenite, the cells undergo an EMT and show enhanced invasion and migration. With longer times for transformation of HBE cells, there was increased miR-21 expression. Further, during the transformation of HBE cells, inhibition of miR-21 with an miR-21 inhibitor increased levels of PDCD4, an inhibitor of neoplastic transformation; reduced Twist1, a transcription factor involved in cell differentiation; and inhibited cell invasion and migration. In addition, PDCD4 interacted with Twist1 and inhibited its expression function, which is involved in arsenite-induced EMT. Thus, miR-21, acting on PDCD4, which interacts with Twist1 and represses the expression of Twist1, contributes to the EMT induced by arsenite. These observations add to an understanding of the processes involved in arsenite-induced carcinogenesis.
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Luo
authors.affiliation: The First Clinic Medical College, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ji
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Department of Occupational and Environmental Health, School of Public Health, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
authors.forename: Jinfei
authors.initials: J
authors.lastname: Jing
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Bairu
authors.initials: B
authors.lastname: Wang
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Wenchao
authors.initials: W
authors.lastname: Xu
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Le
authors.initials: L
authors.lastname: Shi
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Institute of Toxicology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029,PR China; The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, PR China. Electronic address: drqzliu@hotmail.com.
authors.forename: Qizhan
authors.initials: Q
authors.lastname: Liu
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D018053:Arsenites / Q000633:toxicity*; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D017670:Sodium Compounds / Q000633:toxicity*; D013997:Time Factors; D014162:Transfection; D051879:Twist-Related Protein 1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D018053:Arsenites; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; C114487:PDCD4 protein, human; D016601:RNA-Binding Proteins; D017670:Sodium Compounds; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; C017947:sodium arsenite
keywords: Arsenite; Carcinogenesis; Epithelial–mesenchymal transition (EMT); miRNA-21