Suppressive effect of global DNA hypomethylation on gastric carcinogenesis

Abstract

Global DNA hypomethylation and concomitant site-specific gene hypermethylation are among the most common molecular alterations in human neoplasia. Although site-specific DNA hypermethylation has been shown to be associated with the development of various tumors accompanied by transcriptional silencing of target genes, the functional significance of global DNA hypomethylation in tumorigenesis remains unclear. Previous studies have revealed that a genetic reduction of the DNA methylation levels leads to opposing effects on tumor development, depending on the tumor cell type and the stage of tumorigenesis. In the present study, we investigated the effect of DNA hypomethylation on gastric carcinogenesis in mice. The genetic reduction of DNA methylation levels suppressed the incidence, number and size of gastric tumors in two different mouse models for gastric tumorigenesis: the N-methyl-N-nitrosourea-induced model and the Apc(Min/+) mouse model that spontaneously develops gastric tumors with aging. Histological analyses revealed DNA hypomethylation to completely inhibit the development of invasive gastric tumors. These findings indicate that the reduction of DNA methylation levels suppresses gastric carcinogenesis and suggest that DNA methylation is closely associated with gastric tumorigenesis.