Expression Characteristics of Genes Hypermethylated and Downregulated in Rat Liver Specific to Non-genotoxic Hepatocarcinogens.

Expression Characteristics of Genes Hypermethylated and Downregulated in Rat Liver Specific to Non-genotoxic Hepatocarcinogens.

Toxicol Sci. 2019 Jan 25;:

Authors: Ito Y, Nakajima K, Masubuchi Y, Kikuchi S, Saito F, Akahori Y, Jin M, Yoshida T, Shibutani M

Abstract
The present study examined hypermethylated and downregulated genes specific to carbon tetrachloride (CCl4) by Methyl-Seq analysis combined with expression microarray analysis in the liver of rats treated with CCl4 or N-nitrosodiethylamine (DEN) for 28 days, by excluding those with DEN. Among 52 genes, Ldlrad4, Proc, Cdh17 and Nfia were confirmed to show promoter-region hypermethylation by methylation-specific quantitative PCR analysis on day 28. The transcript levels of these four genes decreased by real-time reverse transcription-PCR analysis in the livers of rats treated with non-genotoxic hepatocarcinogens for up to 90 days compared with untreated controls and genotoxic hepatocarcinogens. Immunohistochemically, LDLRAD4 and PROC showed decreased immunoreactivity, forming negative foci, in glutathione S-transferase placental form (GST-P)+ foci, and incidences of LDLRAD4- and PROC- foci in GST-P+ foci induced by treatment with non-genotoxic hepatocarcinogens for 84 or 90 days were increased compared with those with genotoxic hepatocarcinogens. In contrast, CDH17 and NFIA responded to hepatocarcinogens without any relation to the genotoxic potential of carcinogens. All four genes did not respond to renal carcinogens after treatment for 28 days. Considering that Ldlrad4 is a negative regulator of transforming growth factor-β signaling, Proc participating in p21WAF1/CIP1 upregulation by activation, Cdh17 inducing cell cycle arrest by gene knockdown, and Nfia playing a role in a tumor-suppressor, all these genes may be potential in vivo epigenetic markers of non-genotoxic hepatocarcinogens from the early stages of treatment in terms of gene expression changes. LDLRAD4 and PROC may have a role in the development of preneoplastic lesions produced by non-genotoxic hepatocarcinogens.

PMID: 30690589 [PubMed - as supplied by publisher]

from A via a.sfakia on Inoreader http://bit.ly/2D1SbDJ