Suppression of tumor suppressor Tsc2 and DNA repair glycosylase Nthl during spontaneous liver tumorigenesis in Long-Evans Cinnamon rats

Chronic inflammation and oxidative stress are arguably associated with an increased risk of cancer. Certain diseases that are characterized by oxyradical overload, such as Wilson's disease (WD), have also been associated with a higher risk of liver cancer. The Long-Evans Cinnamon (LEC) rat, an...

Full description

Saved in:
Bibliographic Details
Published in:Molecular and cellular biochemistry 2010-05, Vol.338 (1-2), p.233
Main Authors: Sajankila, Shyama Prasad, Manthena, Praveen V, Adhikari, Sanjay, Choudhury, Sujata, Izumi, Keisuke, Roy, Rabindra
Format: Article
Language:English
Subjects:
DNA
DNA repair
Gene expression
Health aspects
Hepatitis
Inflammation
Liver cancer
Protein binding
Proteins
RNA
Tuberous sclerosis
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Chronic inflammation and oxidative stress are arguably associated with an increased risk of cancer. Certain diseases that are characterized by oxyradical overload, such as Wilson's disease (WD), have also been associated with a higher risk of liver cancer. The Long-Evans Cinnamon (LEC) rat, an animal model for WD, is genetically predisposed to the spontaneous development of liver cancer and has been shown to be very useful for studying the mechanisms of inflammation-mediated spontaneous carcinogenesis. Endonuclease III (Nth1) plays a significant role in the removal of oxidative DNA damage. Nth1 and a tumor suppressor gene Tuberous sclerosis 2 (Tsc2) are bidirectionally regulated in humans, mice, and rats by a common minimal promoter containing two Ets-binding sites (EBSs). In this study, we examined the expression of Nth1 and Tsc2 genes during disease progression in the LEC rat liver. During the period of acute hepatitis (16-17 weeks), we observed decreased Nth1 and Tsc2 mRNA levels and a continued decrease of the Tsc2 gene in 24 weeks in LEC rats, while the effect was minimal in Long-Evans Agouti (LEA) rats. This reduction in the mRNA levels was due to the reduced binding of EBSs in the Nth1/Tsc2 promoter. Increase in protein oxidation (carbonyl content) during the same time period (16-24 weeks) may have an effect on the promoter binding of regulatory proteins and consequent decrease in Nth1 and Tsc2 gene expressions during tumorigenesis. Keywords Long-Evans Cinnamon rat * Long-Evans Agouti rat * Reactive oxygen species * Wilson's disease * Liver cancer * Hepatitis
ISSN:0300-8177
DOI:10.1007/s11010-009-0357-1