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

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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.

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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

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Acknowledgments

We thank Drs. Duanjun Tan and Catalin Marian in Prof. Peter Shield’s Laboratory for initial help in real-time PCR experiments. We also thank Mr. Cliff Chung for expert editorial help. The work was supported by National Institutes of Health grants RO1 CA 113447 (RR).

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Authors and Affiliations

  1. Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical School, LL level, S-122, 3800 Reservoir Road, NW, Washington, 20057, DC, USA

    Shyama Prasad Sajankila, Praveen V. Manthena, Sanjay Adhikari, Sujata Choudhury & Rabindra Roy

  2. Department of Molecular and Environmental Pathology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan

    Keisuke Izumi

Authors
  1. Shyama Prasad Sajankila
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  2. Praveen V. Manthena
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  3. Sanjay Adhikari
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  4. Sujata Choudhury
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  5. Keisuke Izumi
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  6. Rabindra Roy
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Correspondence to Rabindra Roy.

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Sajankila, S.P., Manthena, P.V., Adhikari, S. et al. Suppression of tumor suppressor Tsc2 and DNA repair glycosylase Nth1 during spontaneous liver tumorigenesis in Long-Evans Cinnamon rats. Mol Cell Biochem 338, 233–239 (2010). https://doi.org/10.1007/s11010-009-0357-1

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  • DOI: https://doi.org/10.1007/s11010-009-0357-1

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