CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life

By Sailaja V. Elchuri, T. Oberley, W. Qi, R. Eisenstein, L. Roberts, H. Remmen, C. Epstein, Ting-Ting Huang. Oncogene, 2005

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Mice deficient in CuZn superoxide dismutase (CuZnSOD) 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.

Subfields: Molecular Biology, Nutrition and Dietetics, Rheumatology

View Paper: https://www.semanticscholar.org/paper/12873b563157e9c2b7898d7b3156384b9708a2de

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Citations in the corpus

Oxidative stress in the pathogenesis of skin disease. (2006, background): “The tumor yield or incidence in two-stage skin chemical carcinogenesis in mice overexpressing CuZnSOD or glutathione peroxidase or both was found to be no different from that observed in their wild-type littermates (Lu et al., 1997; Elchuri et al., 2005).”
Trends in oxidative aging theories. (2007, background): “The phenotype of Ku86 −/− mice in a pure C57B6/J background is considerably worse (the above results were conducted in mixed backgrounds), with very few surviving longer than a month after birth.”
Reactive Species and Antioxidants. Redox Biology Is a Fundamental Theme of Aerobic Life (2006, background): “They have reproductive problems and show impaired vascular function (Elchuri et al., 2005).”
A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. (2011, background): “Mice lacking SOD1 have persistent and widespread oxidative damage throughout their life span and develop hepatocellular carcinoma (Elchuri et al., 2005).”
Copper homeostasis and cuproptosis in health and disease (2022, background): “DNA mutations,(35) and SOD1 knockout mice develop hepatocellular carcinoma, presumably as a result of oxidative damage of hepatocytes.(36) Moreover, CCS expression is regulated by cellular Cu status; when Cu content decreases, CCS levels increase, and when Cu content is high, the degradation of CCS ”
Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling (2018, positive): “Sod1−/− mice, as expected, showed extensive oxidative damage in the cytoplasm as well as to a lesser extent in the nucleus and mitochondria (Elchuri et al., 2005).”
Mechanisms for copper acquisition, distribution and regulation. (2008, background): “, and Sod1 −/− mice develop hepatocellular carcinom”
Oxidative Stress, Mitochondrial Dysfunction, and Aging (2011, background): “Mice lacking the antioxidant enzyme superoxide dismutase 1 (SOD1) exhibit a 30% decrease in life expectancy [56].”
Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach? (2009, background): “Animal studies using either gene knockout or transgenic overexpression approaches demonstrated a potential role for antioxidant molecules, such as SOD, glutathione peroxidases and peroxiredoxin as tumour suppressor”
Redox Regulation of Cell Survival (2008, positive): “The aged mice have elevated oxidative damage to lipid, protein, and DNA, which are associated with increased apoptosis and reduced life span (78).”