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Oxidative stress is arguably the most important cause of cellular genotoxicity, which is thought to cause diseases such as cancer and neurological disorders. Recent studies have linked oxidative stress and chronic inflammation with an increased risk of cancer. Certain diseases, characterized by oxyradical overload, such as Wilson’s disease (WD) also have been associated with the higher risk of liver cancer. The Long Evans Cinnamon (LEC) rat, an animal model for WD, proved to be very useful in studying mechanisms of spontaneous carcinogenesis. LEC rats are a mutant strain of Long-Evans rats and are genetically predisposed to spontaneous HCCs as compared with the wild-type control Long Evans Agouti (LEA) rats. Because of the genetic copper metabolism disorder LEC rats develop hepatitis 4 months after birth, followed by chronic hepatitis later in life, and eventually all of the surviving animals from liver injury and hepatitis develop spontaneous hepatocellular carcinomas. Thus, the LEC rats having this genetically induced oxidative condition are also found to be very useful model in our laboratory for the study of repair of endogenous DNA lesions and their relation to spontaneous carcinogenesis. Previously we have shown that the repair excision activity of mutagenic oxidized bases, mediated by DNA glycosylases such as NTH1, was significantly altered at different stages of HCC development in LEC rats compared to the control LEA rats (Choudhury et. al. Cancer Res. 63:7704, 2003). In addition to the alteration of enzymatic activity, mRNA level of NTH1 was also modulated significantly in LEC rat liver during tumorigenesis. This prompted us to elucidate the transcriptional regulatory mechanism of NTH1 expression in LEC rat liver during tumorigenesis. We have found that at different ages the expression profile of NTH1 in LEC and LEA rat livers is appreciably correlated with the activity pattern of NTH1. In LEC rat liver the expression of NTH1 mRNA was significantly decreased during acute hepatitis period and prior to the formation of preneoplastic foci. Moreover, the Electrophoretic Mobility Shift Assay revealed the binding of specific proteins to the Ets binding sites (EBS) in the the NTH1 promoter sequences. Notably, the EBS-protein complexes were significantly decreased at the same time period (acute hepatitis) in LEC rat liver and appear to be correlated with the expression of NTH1 gene. Furthermore, among the Ets family proteins, Eif-1 or related factors were found to play a major role in regulation of NTH1 gene expression during liver tumorigenesis in LEC rats (RO1 CA 92306).

[Proc Amer Assoc Cancer Res, Volume 46, 2005]