Calvisi, Diego Francesco and Ladu, Sara and Hironaka, Koji and Factor, Valentina M. and Thorgeirsson, Snorri S. (2004) Vitamin E down-modulates iNOS and NADPH oxidase in c-Myc/TGF-alpha transgenic mouse model of liver cancer. Journal of Hepatology, Vol. 41 (5), p. 815-822. ISSN 0168-8278. Article.
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Background/Aims. Co-expression of c-Myc and TGF-α in the mouse liver accelerates hepatocarcinogenesis and enhances DNA damage due to chronic oxidative stress. Dietary supplementation with vitamin E (VE) inhibits hepatocarcinogenesis and reduces chromosomal alterations in the same mice. Here we investigated the sources of reactive oxygen species (ROS) production in c-Myc/TGF-α transgenic mice. Methods. Inducible nitric oxide synthase (iNOS) and NADPH oxidase levels were determined in c-Myc, TGF-α and c-Myc/TGF-α mice by RT-PCR, western blot analysis and immunohistochemistry. Results. iNOS and nitrotyrosines levels were higher in the three transgenic lines when compared with wild-type mice. Preneoplastic and neoplastic lesions from c-Myc, TGF-α and c-Myc/TGF-α transgenic mice displayed upregulation of NADPH oxidase subunits p47-, 67-phox, Rac1, HSP 70, and HO-1. Importantly, dietary supplementation with vitamin E abolished iNOS expression, lowered nitrotyrosines, p47-, p67-phox, and Rac1 levels, and suppressed HSP 70 and HO-1 proteins in c-Myc/TGF-α livers. Conclusions. The results suggest that iNOS and NADPH oxidase are involved in ROS generation during c-Myc/TGF-α hepatocarcinogenesis and are inhibited by VE treatment. The data provide additional evidence for the potential use of VE in treatment of chronic liver diseases and HCC prevention.
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