TNF-alpha induced DNA damage in primary murine hepatocytes

Nicholas M Wheelhouse, Yuen-Sum Chan, Sheona E Gillies, Helen Caldwell, James A Ross, David J Harrison, Sandrine Prost

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, usually arising from a background of chronic inflammatory disease. Tumor necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine produced in response to tissue injury, endotoxin exposure or infection and TNF-alpha signalling in hepatocytes is associated with an increase in oxidative stress. DNA is vulnerable to reactive oxygen species (ROS)-induced damage, which is highly mutagenic. Cells respond to DNA damage through the stabilisation of the tumor suppressor p53, which maintains genomic fidelity through induction of a cell cycle arrest in order to allow repair or elimination of the damaged cell through apoptosis. This study was carried out to determine if TNF-alpha caused oxidative DNA damage in primary cultures of murine hepatocytes and whether any damage would result in the induction of the tumor suppressor p53 and cell-cycle arrest. Using a modified Comet assay, to measure DNA damage we have demonstrated that TNF-alpha causes the formation of 8-oxo-deoxyguanosine (8-oxodG), an established marker of oxidative DNA damage, and a lesion associated with chronic hepatitis in human livers. In addition, the increase in DNA damage did not result in p53 stabilisation and TNF-alpha caused an increase in cell-cycle progression. We believe that this study indicates a possible putative role for TNF-alpha in the early stages of malignant transformation of hepatocytes.
Original languageEnglish
Pages (from-to)889-94
Number of pages6
JournalInternational Journal of Molecular Medicine
Volume12
Issue number6
Publication statusPublished - 2003

Keywords / Materials (for Non-textual outputs)

  • Animals
  • Antineoplastic Agents
  • Apoptosis
  • Cell Division
  • DNA Damage
  • Hepatocytes
  • Mice
  • Oxidation-Reduction
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha

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