在c-Myc/TGF-α转基因肝癌小鼠模型中，维生素E下调诱导型一氧化氮合酶和NADPH氧化酶。

Vitamin E down-modulates iNOS and NADPH oxidase in c-Myc/TGF-alpha transgenic mouse model of liver cancer.

作者信息

Calvisi Diego F, Ladu Sara, Hironaka Koji, Factor Valentina M, Thorgeirsson Snorri S

机构信息

Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 37, Room 4146A1, 37 Convent Drive MSC 4262, Bethesda, MD 20892-4258, USA.

出版信息

J Hepatol. 2004 Nov;41(5):815-22. doi: 10.1016/j.jhep.2004.07.030.

DOI:10.1016/j.jhep.2004.07.030

PMID:15519655

Abstract

BACKGROUND/AIMS: Co-expression of c-Myc and TGF-alpha 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-alpha transgenic mice.

METHODS

Inducible nitric oxide synthase (iNOS) and NADPH oxidase levels were determined in c-Myc, TGF-alpha and c-Myc/TGF-alpha 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-alpha and c-Myc/TGF-alpha 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-alpha livers.

CONCLUSIONS

The results suggest that iNOS and NADPH oxidase are involved in ROS generation during c-Myc/TGF-alpha 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.

摘要

背景/目的：c-Myc和转化生长因子α（TGF-α）在小鼠肝脏中的共表达加速了肝癌发生，并增强了由慢性氧化应激导致的DNA损伤。在相同小鼠中，膳食补充维生素E（VE）可抑制肝癌发生并减少染色体改变。在此，我们研究了c-Myc/TGF-α转基因小鼠中活性氧（ROS）产生的来源。

方法

通过逆转录聚合酶链反应（RT-PCR）、蛋白质免疫印迹分析和免疫组织化学法，测定c-Myc、TGF-α和c-Myc/TGF-α小鼠中诱导型一氧化氮合酶（iNOS）和NADPH氧化酶水平。

结果

与野生型小鼠相比，三种转基因品系中的iNOS和硝基酪氨酸水平更高。c-Myc、TGF-α和c-Myc/TGF-α转基因小鼠的癌前病变和肿瘤病变显示NADPH氧化酶亚基p47-、67-吞噬细胞氧化酶、Rac1、热休克蛋白70（HSP 70）和血红素加氧酶-1（HO-1）上调。重要的是，膳食补充维生素E可消除c-Myc/TGF-α肝脏中的iNOS表达，降低硝基酪氨酸、p47-、p67-吞噬细胞氧化酶和Rac1水平，并抑制HSP 70和HO-1蛋白。