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

Abstract

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.