miR-190-mediated downregulation of PHLPP contributes to arsenic-induced Akt activation and carcinogenesis

Toxicol Sci. 2011 Oct;123(2):411-20. doi: 10.1093/toxsci/kfr188. Epub 2011 Jul 12.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Arsenic Poisoning
  • Arsenic Trioxide
  • Arsenicals
  • Bronchi / drug effects
  • Bronchi / pathology
  • Carcinogens, Environmental / toxicity*
  • Cell Line
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / chemically induced
  • Down-Regulation / drug effects*
  • Epithelial Cells / drug effects
  • Epithelial Cells / pathology
  • Gene Expression Regulation / drug effects*
  • Gene Silencing
  • Humans
  • MicroRNAs / biosynthesis*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oxides / toxicity*
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • RNA, Messenger / metabolism
  • Talin / genetics
  • Talin / metabolism

Substances

  • Arsenicals
  • Carcinogens, Environmental
  • MicroRNAs
  • Nuclear Proteins
  • Oxides
  • RNA, Messenger
  • TLN2 protein, human
  • Talin
  • PHLPP1 protein, human
  • Phosphoprotein Phosphatases
  • Arsenic Trioxide