Molecular and Cellular Biochemistry

, Volume 338, Issue 1, pp 233–239

Suppression of tumor suppressor Tsc2 and DNA repair glycosylase Nth1 during spontaneous liver tumorigenesis in Long-Evans Cinnamon rats

  • Shyama Prasad Sajankila
  • Praveen V. Manthena
  • Sanjay Adhikari
  • Sujata Choudhury
  • Keisuke Izumi
  • Rabindra Roy
Article

DOI: 10.1007/s11010-009-0357-1

Cite this article as:
Sajankila, S.P., Manthena, P.V., Adhikari, S. et al. Mol Cell Biochem (2010) 338: 233. doi:10.1007/s11010-009-0357-1

Abstract

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 bi-directionally 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 

Abbreviations

LEC

Long-Evans Cinnamon rat

LEA

Long-Evans Agouti rat

Nth1

Endonuclease III

ROS

Reactive oxygen species

WD

Wilson’s disease

OGG1

8-Oxoguanine DNA glycosylase

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Shyama Prasad Sajankila
    • 1
  • Praveen V. Manthena
    • 1
  • Sanjay Adhikari
    • 1
  • Sujata Choudhury
    • 1
  • Keisuke Izumi
    • 2
  • Rabindra Roy
    • 1
  1. 1.Department of Oncology, Lombardi Comprehensive Cancer CenterGeorgetown University Medical SchoolWashingtonUSA
  2. 2.Department of Molecular and Environmental Pathology, Institute of Health BiosciencesThe University of Tokushima Graduate SchoolTokushimaJapan

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