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miR-190-Mediated Downregulation of PHLPP Contributes to Arsenic-Induced Akt Activation and Carcinogenesis

2011; Oxford University Press; Volume: 123; Issue: 2 Linguagem: Inglês

10.1093/toxsci/kfr188

1096-6080

Kevin Beezhold, Jia Liu, Hong Kan, Terry Meighan, Vince Castranova, Xianglin Shi, Fei Chen,

RNA Research and Splicing

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.