Kevin Beezhold, Jia Liu, Hong Kan, Terry Meighan, Vince Castranova, Xianglin Shi, Fei Chen
The Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA.
Toxicological sciences : an official journal of the Society of Toxicology 2011 OctThe 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.
Kevin Beezhold, Jia Liu, Hong Kan, Terry Meighan, Vince Castranova, Xianglin Shi, Fei Chen. miR-190-mediated downregulation of PHLPP contributes to arsenic-induced Akt activation and carcinogenesis. Toxicological sciences : an official journal of the Society of Toxicology. 2011 Oct;123(2):411-20
PMID: 21750348
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