CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life
CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life
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DOI：
10.1038/sj.onc.1208207
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发表时间：
2005-01-13
期刊：
影响因子：
8
通讯作者：
Huang, TT
中科院分区：
文献类型：
--
作者：
Elchuri, S;Oberley, TD;Huang, TT
缺乏CuZN超氧化物歧化酶(CuZN-SOD)的小鼠在发育和成年早期没有明显的异常，但寿命缩短，肝脏肿瘤性变化的发生率增加。超过70%的SOD1-/-小鼠发展为结节状增生或肝细胞癌(HCC)。从SOD1-/-和年龄匹配的+/+对照组收集的肝脏的横断面研究表明，早在3个月大的时候，细胞质中就有广泛的氧化损伤，在较小程度上，在细胞核和线粒体中也有。在所检测的所有年龄组的SOD-/-小鼠中，观察到胞浆乌头酸酶显著降低，8-氧-DG和F2-异前列腺素水平升高，谷胱甘肽过氧化物酶活性和孔蛋白水平适度降低。在生化变化的同时，DNA修复酶APEX1、细胞周期控制蛋白Cyclin D1和D3以及肝细胞生长因子受体Met的表达也呈进行性升高。在大分子持续氧化损伤的情况下，细胞增殖增加可能会在以后的生活中导致肝癌的发生。
Mice deficient in CuZn superoxide dismutase (CuZn-SOD) showed no overt abnormalities during development and early adulthood, but had a reduced lifespan and increased incidence of neoplastic changes in the liver. Greater than 70% of Sod1-/- mice developed liver nodules that were either nodular hyperplasia or hepatocellular carcinoma (HCC). Cross-sectional studies with livers collected from Sod1-/- and age-matched +/+ controls revealed extensive oxidative damage in the cytoplasm and, to a lesser extent, in the nucleus and mitochondria from as early as 3 months of age. A marked reduction in cytosolic aconitase, increased levels of 8-oxo dG and F2-isoprostanes, and a moderate reduction in glutathione peroxidase activities and porin levels were observed in all age groups of Sod1-/- mice examined. There were also age-related reductions in Mn superoxide dismutase activities and carbonic anhydrase III. Parallel to the biochemical changes, there were progressive increases in the DNA repair enzyme APEX1, the cell cycle control proteins cyclin D1 and D3, and the hepatocyte growth factor receptor Met. Increased cell proliferation in the presence of persistent oxidative damage to macromolecules likely contributes to hepatocarcinogenesis later in life.