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

Abstract

21104 Background: It is estimated that chronic inflammation is an important underlying condition for sporadic human tumor development, accounting for approximately 20% of human cancers. TNFa is an inflammation cytokine playing an important role in inflammation- associated cancers. However, the underlying mechanism of how TNFa leads to cancer is not clear. Before we initiated this study, TNFa is not known to have a direct effect on DNA. Methods: We studied genetic mutations, cellular transformation in cells and mice treated with TNFa. DNA damages and genetic aberrations caused by TNFa treatment were measured by gene amplification assay, micronucleus assay, cytogenetic analysis for chromosomal aberrations and immunostaining of 8-OHdG (8-hydroxydeoxyguanine; marker for DNA damage and oxidative stress). Cellular transformation was studied by standard transformation assay using mouse embryo fibroblast cells. Results: In this study, we found that TNFa can cause DNA damages through induction of reactive oxygen species (ROS). Our findings include: (1) The mutagenic effect of TNFa is comparable to that of ionizing radiation. TNFa treatment in cultured cells resulted in increased gene amplification, micronuclei formation and chromosomal instability. (2) Antioxidants significantly reduced TNFa-induced genetic mutations. (3) TNFa also induced oxidative stress and nucleotide damages in mouse tissues in vivo. (4) Moreover, TNFa treatment alone led to increased malignant transformation of mouse embryo fibroblasts, which could be partially suppressed by antioxidants. (5) The mutagenic effect of TNFa is independent that of NF?B which was shown to be a mediator in inflammation-associated cancers. Conclusions: As TNFa is known to be 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 TNFa promotes cancer development through induction of gene mutations, in addition to the previously reported mechanisms in which NF-?B activation was implicated. No significant financial relationships to disclose.