Tumor necrosis factor-α is a potent endogenous mutagen that promotes cellular transformation

被引:131
作者
Yan, Bin
Wang, Huili
Rabbani, Zahid N.
Zhao, Yulin
Li, Wenrong
Yuan, Yuqing
Li, Fang
Dewhirst, Mark W.
Li, Chuan-Yuan
机构
[1] Univ Colorado, Hlth Sci Ctr, Dept Radiat Oncol, Aurora, CO 80045 USA
[2] Duke Univ, Dept Radiat Oncol, Med Ctr, Durham, NC USA
[3] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
关键词
D O I
10.1158/0008-5472.CAN-06-2540
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Tumor necrosis factor-alpha (TNF-alpha) is an important inflammation cytokine without known direct effect on DNA. In this study, we found that TNF-alpha can cause DNA damages through reactive oxygen species. The mutagenic effect of TNF-alpha is comparable with that of ionizing radiation. TNF-alpha treatment in cultured cells resulted in increased gene mutations, gene amplification, micronuclei formation, and chromosomal instability. Antioxidants significantly reduced TNF-alpha-induced genetic damage. TNF-alpha also induced oxidative stress and nucleotide damages in mouse tissues in vivo. Moreover, TNF-alpha treatment alone led to increased malignant transformation of mouse embryo fibroblasts, which could be partially suppressed by antioxidants. As TNF-alpha 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-alpha promotes cancer development through induction of gene mutations, in addition to the previously reported mechanisms, in which nuclear factor-kappa B activation was implicated.
引用
收藏
页码:11565 / 11570
页数:6
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