miR-190-mediated downregulation of PHLPP contributes to arsenic-induced Akt activation and carcinogenesis.
Beezhold-K; Liu-J; Kan-H; Meighan-T; Castranova-V; Shi-X; Chen-F
Toxicol Sci 2011 Jul; 123(2):411-420
The role of trivalent arsenic (As3+) 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 As3+ is a potent inducer for the expression of miR-190 in human bronchial epithelial cells. The induction of miR-190 by As3+ 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 As3+ 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 As3+ -induced carcinogenesis.
Biological-effects; Biological-factors; Carcinogenesis; Cell-biology; Cellular-reactions; Cytology; Genotoxic-effects; Pulmonary-disorders; Pulmonary-system; Pulmonary-system-disorders; Respiratory-system-disorders; Statistical-analysis;
Author Keywords: arsenite; microRNA; Akt; carcinogenesis
Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201