TNF-α induced DNA damage in primary murine hepatocytes

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

Abstract

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.

Citation

Chan, Y.-S., Gillies, S., Ross, J., Harrison, D., Wheelhouse, N., Chan, Y.-S., Gillies, S. E., Caldwell, H., Ross, J. A., Harrison, D. J., & Prost, S. (2003). TNF-α induced DNA damage in primary murine hepatocytes. International Journal of Molecular Medicine, 12(6), 889-894. https://doi.org/10.3892/ijmm.12.6.889

• Journal Article Type: Article
• Online Publication Date: Dec 1, 2003
• Publication Date: 2003-12
• Deposit Date: Jul 21, 2016
• Journal: International Journal of Molecular Medicine
• Print ISSN: 1107-3756
• Electronic ISSN: 1791-244X
• Publisher: Spandidos Publications
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 6
• Pages: 889-894
• DOI: https://doi.org/10.3892/ijmm.12.6.889
• Keywords: DNA damage, TNF-alpha, hepatocytes,
• Public URL: http://researchrepository.napier.ac.uk/Output/304755
• Related Public URLs: http://www.spandidos-publications.com/ijmm/12/6/889https://www.spandidos-publications.com/ijmm/12/6/889