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Tumor Necrosis Factor- Is a Potent Endogenous Mutagen that Promotes Cellular Transformation

Departments of ¹ Radiation Oncology and ² Medicine, Duke University Medical Center, Durham, North Carolina and ³ Department of Radiation Oncology, University of Colorado Health Sciences Center, Aurora, Colorado

Requests for reprints: Chuan-Yuan Li, Department of Radiation Oncology, University of Colorado Health Sciences Center, P.O. Box 6511, Mail Stop 8123, Aurora, CO 80045. Phone: 303-724-1542; Fax: 303-724-1554; E-mail: Chuan.Li{at}UCHSC.edu.

Tumor necrosis factor- (TNF-) is an important inflammation cytokine without known direct effect on DNA. In this study, we found that TNF- can cause DNA damages through reactive oxygen species. The mutagenic effect of TNF- is comparable with that of ionizing radiation. TNF- treatment in cultured cells resulted in increased gene mutations, gene amplification, micronuclei formation, and chromosomal instability. Antioxidants significantly reduced TNF-–induced genetic damage. TNF- also induced oxidative stress and nucleotide damages in mouse tissues in vivo. Moreover, TNF- treatment alone led to increased malignant transformation of mouse embryo fibroblasts, which could be partially suppressed by antioxidants. As TNF- is involved in chronic inflammatory diseases, such as chronic hepatitis, ulcerative colitis, and chronic skin ulcers, and these diseases predispose the patients to cancer development, our results suggest a novel pathway through which TNF- promotes cancer development through induction of gene mutations, in addition to the previously reported mechanisms, in which nuclear factor-B activation was implicated. (Cancer Res 2006; 66(24): 11565-70)

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