Second Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama, 641-0012, Japan,
Gastric Cancer. 2013 Oct;16(4):488-97. doi: 10.1007/s10120-012-0230-x. Epub 2013 Jan 6.
Chronic inflammation triggered by Helicobacter pylori causes altered DNA methylation in stomach mucosae, which is deeply involved in gastric carcinogenesis. This study aimed to elucidate the correlation between altered mucosal DNA methylation levels and activity of H. pylori-related gastritis, because inflammatory activity shows particular correlations with the development of diffuse-type cancer.
Methylation levels in stomach mucosae of 78 healthy volunteers were determined by real-time methylation-specific PCR or bisulfite pyrosequencing. Examined loci were the promoter CpG islands of six genes (FLNc, HAND1, THBD, p41ARC, HRASLS, and LOX) and the CpG sites of non-coding repetitive elements (Alu and Satα) that are reportedly altered by H. pylori infection. Activity of H. pylori-related gastritis was evaluated using two serum markers: H. pylori antibody titer and pepsinogen II.
Methylation levels of the six CpG islands were consistently increased, and those of the two repetitive elements were consistently decreased in a stepwise manner with the activity of gastric inflammation as represented by serum marker levels. Each serum marker level was well correlated with the overall DNA methylation status of stomach mucosa, and these two serologic markers were additive in the detection of the mucosa with severely altered DNA methylation.
Alteration in mucosal DNA methylation level was closely correlated with activity of H. pylori-related gastritis as evaluated by serum markers. The observed correlation between altered DNA methylation levels and activity of H. pylori-related gastritis appears to be one of the relevant molecular mechanisms underlying the development of diffuse-type cancer.
幽门螺杆菌引起的慢性炎症会导致胃黏膜中的 DNA 甲基化改变，这与胃癌的发生密切相关。本研究旨在阐明黏膜 DNA 甲基化水平改变与幽门螺杆菌相关性胃炎活动之间的相关性，因为炎症活性与弥漫型癌症的发展具有特殊的相关性。
通过实时甲基化特异性 PCR 或亚硫酸氢盐焦磷酸测序法测定 78 名健康志愿者胃黏膜中的甲基化水平。检测的位点是六个基因（FLNc、HAND1、THBD、p41ARC、HRASLS 和 LOX）的启动子 CpG 岛，以及据报道受幽门螺杆菌感染改变的非编码重复元件（Alu 和 Satα）的 CpG 位点。幽门螺杆菌相关性胃炎的活性采用两种血清标志物进行评估：幽门螺杆菌抗体滴度和胃蛋白酶原 II。
随着血清标志物代表的胃炎症活性的增加，六个 CpG 岛的甲基化水平呈逐步增加趋势，而两个重复元件的甲基化水平则呈逐步降低趋势。每个血清标志物水平与胃黏膜的总体 DNA 甲基化状态密切相关，这两种血清标志物在检测严重改变 DNA 甲基化的黏膜方面具有相加作用。
胃黏膜 DNA 甲基化水平的改变与血清标志物评估的幽门螺杆菌相关性胃炎活动密切相关。观察到的 DNA 甲基化水平改变与幽门螺杆菌相关性胃炎活动之间的相关性可能是弥漫型癌症发生的相关分子机制之一。
