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

Oncogene volume 24, pages 367–380 (2005)Cite this article

Abstract

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.

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Acknowledgements

We thank Anna Bogdanova and Xinli Wong for excellent animal care, Aaron Tward and Sanja Kakar for helpful discussion, and Charles Limoli for critical reading of the manuscript. This work was supported by funding from the Stanford Cancer Council (TTH), American Cancer Society (HVR), and the National Institutes of Health AG16633 (TTH), AG16998 (CJE), DK47219 (RSE), GM42056 (MERIT Award to LJR), GM15431 (LJR), and DK26657 (LJR), and resources and the use of facilities at the Palo Alto VA Health Care System, Palo Alto, CA (TTH) and the William S Middleton Memorial Veterans Administration Hospital, Madison, WI (TDO).

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Authors and Affiliations

  1. Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA

    Sailaja Elchuri & Ting-Ting Huang

  2. Department of Pathology, University of Wisconsin, Madison, WI, 53706, USA

    Terry D Oberley

  3. Pathology Service, VA Hospital, Madison, WI, 53705, USA

    Terry D Oberley

  4. Department of Cellular and Structural Biology, UTHSC, San Antonio, TX, 78229, USA

    Wenbo Qi & Holly Van Remmen

  5. Department of Nutritional Sciences, University of Wisconsin, Madison, WI, 53706, USA

    Richard S Eisenstein

  6. Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, TN, 37232, USA

    L Jackson Roberts

  7. GRECC, Audie Murphy VA Hospital, San Antonio, TX, 78229, USA

    Holly Van Remmen

  8. Department of Pediatrics, University of California, San Francisco, CA, 94341, USA

    Charles J Epstein

  9. GRECC, Palo Alto VA Health Care System, Palo Alto, CA, 94304, USA

    Ting-Ting Huang

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Elchuri, S., Oberley, T., Qi, W. et al. CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24, 367–380 (2005). https://doi.org/10.1038/sj.onc.1208207

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