Induction of epigenetic alterations by chronic inflammation and its significance on carcinogenesis.

Chronic inflammation is deeply involved in development of human cancers, such as gastric and liver cancers. Induction of cell proliferation, production of reactive oxygen species, and direct stimulation of epithelial cells by inflammation-inducing factors have been considered as mechanisms involved. Inflammation-related cancers are known for their multiple occurrences, and aberrant DNA methylation is known to be present even in noncancerous tissues. Importantly, for some cancers, the degree of accumulation has been demonstrated to be correlated with risk of developing cancers. This indicates that inflammation induces aberrant epigenetic alterations in a tissue early in the process of carcinogenesis, and accumulation of such alterations forms "an epigenetic field for cancerization." This also suggests that inhibition of induction of epigenetic alterations and removal of the accumulated alterations are novel approaches to cancer prevention. Disturbances in cytokine and chemokine signals and induction of cell proliferations are important mechanisms of how inflammation induces aberrant DNA methylation. Aberrant DNA methylation is induced in specific genes, and gene expression levels, the presence of RNA polymerase II (active or stalled), and trimethylation of H3K4 are involved in the specificity. Expression of DNA methyltransferases (DNMTs) is not necessarily induced by inflammation, and local imbalance between DNMTs and factors that protect genes from DNA methylation seems to be important.