Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Meguro-ku, Tokyo, Japan.
Cancer Res. 2012 Jul 15;72(14):3445-50. doi: 10.1158/0008-5472.CAN-11-3919. Epub 2012 Jul 3.
Epstein-Barr virus (EBV) establishes latent infection and is associated with tumors, such as Burkitt lymphoma, nasopharyngeal carcinoma, and gastric cancers. We recently reported that EBV(+) gastric cancer shows an EBV(+)/extensively high-methylation epigenotype, and in vitro EBV infection induces extensive DNA methylation with gene repression within 18 weeks. On the basis of the absence of both EBV and high-methylation accumulation in the surrounding mucosa of EBV(+) gastric cancer, it is suggested that an EBV-infected cell acquires extensive methylation to silence multiple tumor suppressor genes in a short time period and transforms into cancer cells, not forming a precancerous field with EBV infection or methylation accumulation. The methylation mechanism induced by EBV infection has not been fully clarified. Differences in EBV genome methylation that are dependent on a different latency status or other epigenomic alterations, such as 3-dimensional conformation and histone modification, may affect host genome methylation. Expressions of viral proteins and small RNAs are also different depending on latency status, and some viral proteins might trigger DNA methylation by inducing DNA methyltransferase overexpression. In this review, we discuss these roles of EBV infection in driving tumorigenesis and their possible association with aberrant DNA methylation.
EB 病毒（EBV）建立潜伏感染，并与肿瘤相关，如伯基特淋巴瘤、鼻咽癌和胃癌。我们最近报道 EBV(+)胃癌表现为 EBV(+)/广泛高甲基化表型，体外 EBV 感染在 18 周内诱导广泛的 DNA 甲基化和基因抑制。鉴于 EBV(+)胃癌周围黏膜中既没有 EBV 也没有高甲基化积累，提示 EBV 感染的细胞在短时间内获得广泛的甲基化，沉默多个肿瘤抑制基因，并转化为癌细胞，而不是形成具有 EBV 感染或甲基化积累的癌前病灶。EBV 感染诱导的甲基化机制尚未完全阐明。依赖于不同潜伏期状态或其他表观遗传改变（如三维构象和组蛋白修饰）的 EBV 基因组甲基化差异可能影响宿主基因组甲基化。病毒蛋白和小 RNA 的表达也因潜伏期状态而异，一些病毒蛋白可能通过诱导 DNA 甲基转移酶过表达引发 DNA 甲基化。在这篇综述中，我们讨论了 EBV 感染在驱动肿瘤发生中的这些作用及其与异常 DNA 甲基化的可能关联。
