Hepatic microRNA profiles offer predictive and mechanistic insights after exposure to genotoxic and epigenetic hepatocarcinogens.

Abstract

In recent years, accumulating evidence supports the importance of microRNAs in liver physiology and disease; however, few studies have examined the involvement of these noncoding genes in chemical hepatocarcinogenesis. Here, we examined the liver microRNA profile of male Fischer rats exposed through their diet to genotoxic (2-acetylaminofluorene) and epigenetic (phenobarbital, diethylhexylphthalate, methapyrilene HCL, monuron, and chlorendic acid) chemical hepatocarcinogens, as well as to non-hepatocarcinogenic treatments (benzophenone, and diethylthiourea) for 3 months. The effects of these treatments on liver pathology, plasma clinical parameters, and liver mRNAs were also determined. All hepatocarcinogens affected the expression of liver mRNAs, while the hepatic microRNA profiles were associated with the mode of action of the chemical treatments and corresponded to chemical carcinogenicity. The three nuclear receptor-activating chemicals (phenobarbital, benzophenone, and diethylhexylphthalate) were characterized by the highly correlated induction of the miR-200a/200b/429, which is involved in protecting the epithelial status of cells and of the miR-96/182 clusters. The four non-nuclear receptor-activating hepatocarcinogens were characterized by the early, persistent induction of miR-34, which was associated with DNA damage and oxidative stress in vivo and in vitro. Repression of this microRNA in a hepatoma cell line led to increased cell growth; thus, miR-34a could act to block abnormal cell proliferation in cells exposed to DNA damage or oxidative stress. This study supports the proposal that hepatic microRNA profiles could assist in the earlier evaluation and identification of hepatocarcinogens, especially those acting by epigenetic mechanisms. © The Author 2012. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved