Mitochondrial Dysfunction Due to Lack of Manganese Superoxide Dismutase Promotes Hepatocarcinogenesis

Antioxid Redox Signal. 2015 Nov 10;23(14):1059-75. doi: 10.1089/ars.2015.6318. Epub 2015 Nov 5.


Aims: One of the cancer hallmarks is mitochondrial dysfunction associated with oxidative stress. Among the first line of defense against oxidative stress is the dismutation of superoxide radicals, which in the mitochondria is carried out by manganese superoxide dismutase (MnSOD). Accordingly, carcinogenesis would be associated with a dysregulation in MnSOD expression. However, the association studies available so far are conflicting, and no direct proof concerning the role of MnSOD as a tumor promoter or suppressor has been provided. Therefore, we investigated the role of MnSOD in carcinogenesis by studying the effect of MnSOD deficiency in cells and in the livers of mice.

Results: We found that loss of MnSOD in hepatoma cells contributed to their conversion toward a more malignant phenotype, affecting all cellular properties generally associated with metabolic transformation and tumorigenesis. In vivo, hepatocyte-specific MnSOD-deficient mice showed changed organ architecture, increased expression of tumor markers, and a faster response to carcinogenesis. Moreover, deficiency of MnSOD in both the in vitro and in vivo model reduced β-catenin and hypoxia-inducible factor-1α levels.

Innovation: The present study shows for the first time the important correlation between MnSOD presence and the regulation of two major pathways involved in carcinogenesis, the Wnt/β-catenin and hypoxia signaling pathway.

Conclusion: Our study points toward a tumor suppressive role of MnSOD in liver, where the Wnt/β-catenin and hypoxia pathway may be crucial elements.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / chemically induced
  • Carcinoma, Hepatocellular / enzymology*
  • Cell Hypoxia
  • Cell Proliferation
  • Cell Shape
  • Cell Transformation, Neoplastic
  • Diethylnitrosamine
  • Hep G2 Cells
  • Hepatocytes / enzymology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Liver Neoplasms, Experimental / enzymology*
  • Male
  • Mice, Knockout
  • Mitochondria / enzymology*
  • Reactive Oxygen Species / metabolism
  • Superoxide Dismutase / physiology*
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism
  • Wnt Signaling Pathway


  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Reactive Oxygen Species
  • 3-nitrotyrosine
  • Diethylnitrosamine
  • Tyrosine
  • Superoxide Dismutase
  • superoxide dismutase 2