Thioredoxin reductase 1 protects against chemically induced hepatocarcinogenesis via control of cellular redox homeostasis

Carcinogenesis. 2012 Sep;33(9):1806-13. doi: 10.1093/carcin/bgs230. Epub 2012 Jul 12.

Abstract

Thioredoxin reductase 1 (TR1) controls the redox state of protein thiols in mammalian cells and has been shown to have roles in both preventing and promoting cancer. To define the role of this selenoenzyme in hepatocellular carcinoma development, we examined tumor incidence in the liver of mice with tissue-specific knockout of mouse TR1 subjected to the liver carcinogen, diethylnitrosamine (DEN). TR1-deficient livers manifested ~90% tumor incidence compared with ~16% in control livers. The TR1-dependent effect was observed independent of sex, and, in control mice, tumorigenesis did not affect the expression of TR1. On the other hand, we observed upregulation of another selenoenzyme, glutathione peroxidase 2 (GPx2), and components of the glutathione (GSH) system, including those that generate reduced GSH. Overall, this study shows that TR1 protects against chemically induced hepatocarcinogenesis via the control of the cellular redox state, whereas its role in promoting this type of cancer is minimal.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Body Weight
  • Female
  • Glutathione / metabolism
  • Glutathione Peroxidase / analysis
  • Homeostasis
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Organ Size
  • Oxidation-Reduction
  • Thioredoxin Reductase 1 / physiology*

Substances

  • glutathione peroxidase GPX1
  • Glutathione Peroxidase
  • Thioredoxin Reductase 1
  • Txnrd1 protein, mouse
  • Glutathione