Suppressive effect of global DNA hypomethylation on gastric carcinogenesis
Suppressive effect of global DNA hypomethylation on gastric carcinogenesis
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DNA整体低甲基化对胃癌发生的抑制作用
DOI：
10.1093/carcin/bgq129
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发表时间：
2010
期刊：
影响因子：
4.7
通讯作者：
Hara A
中科院分区：
文献类型：
--
作者：
Tomita H;Hirata A;Yamada Y;Hata K;Oyama T;Mori H;Yamashita S;Ushijima T;Hara A
整体DNA低甲基化和伴随的位点特异性基因高甲基化是人类肿瘤中最常见的分子改变。虽然位点特异性DNA高甲基化已被证明与各种肿瘤的发展伴随着靶基因的转录沉默，在肿瘤发生中的整体DNA低甲基化的功能意义仍然不清楚。先前的研究表明，DNA甲基化水平的遗传降低导致对肿瘤发展的相反影响，这取决于肿瘤细胞类型和肿瘤发生的阶段。在本研究中，我们研究了DNA低甲基化在小鼠胃癌发生中的作用。DNA甲基化水平的遗传降低抑制了两种不同的胃肿瘤发生小鼠模型中胃肿瘤的发生率、数量和大小：N-甲基-N-亚硝基脲诱导的模型和ApcMin/+小鼠模型，该模型随着年龄的增长自发地发展胃肿瘤。组织学分析显示DNA低甲基化完全抑制浸润性胃肿瘤的发展。这些结果表明，DNA甲基化水平的降低抑制胃癌的发生，并提示DNA甲基化与胃癌的发生密切相关。
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: theN-methyl-N-nitrosourea-induced model and theApcMin/+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.