title: miR-190-mediated downregulation of PHLPP contributes to arsenic-induced Akt activation and carcinogenesis.
abstract: The role of trivalent arsenic (As(3+)) on the regulation of the recently identified noncoding small RNAs, mainly microRNAs, has not been explored so far. In the present study, we provide evidence showing that As(3+) is a potent inducer for the expression of miR-190 in human bronchial epithelial cells. The induction of miR-190 by As(3+) is concentration dependent and associated with the expression of the host gene of miR-190, talin 2, a gene encoding a high-molecular-weight cytoskeletal protein. The elevated level of miR-190 induced by As(3+) is capable of downregulating the translation of the PH domain leucine-rich repeat protein phosphatase (PHLPP), a negative regulator of Akt signaling. Such a downregulation is occurred through direct interaction of the miR-190 with the 3'-UTR region of the PHLPP mRNA, leading to a diminished PHLPP protein expression and consequently, an enhanced Akt activation and expression of vascular endothelial growth factor, an Akt-regulated protein. Overexpression of miR-190 itself is able to enhance proliferation and malignant transformation of the cells as determined by anchorage-independent growth of the cells in soft agar. Accordingly, the data presented suggest that induction of miR-190 is one of the key mechanisms in As(3+)-induced carcinogenesis.
authors.affiliation: The Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Beezhold
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Kan
authors.forename: Terry
authors.initials: T
authors.lastname: Meighan
authors.forename: Vince
authors.initials: V
authors.lastname: Castranova
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
mesh_terms: D020261:Arsenic Poisoning; D000077237:Arsenic Trioxide; D001152:Arsenicals; D001980:Bronchi / Q000187:drug effects / Q000473:pathology; D002274:Carcinogens, Environmental / Q000633:toxicity*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced; D015536:Down-Regulation / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D020868:Gene Silencing; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010087:Oxides / Q000633:toxicity*; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D016608:Talin / Q000235:genetics / Q000378:metabolism
chemical_list: D001152:Arsenicals; D002274:Carcinogens, Environmental; D035683:MicroRNAs; D009687:Nuclear Proteins; D010087:Oxides; D012333:RNA, Messenger; C436513:TLN2 protein, human; D016608:Talin; C400601:PHLPP1 protein, human; D010749:Phosphoprotein Phosphatases; D000077237:Arsenic Trioxide