CpG Methylation and Reduced Expression of O6-Methylguanine DNA Methyltransferase Is Associated With Helicobacter pylori Infection
CpG Methylation and Reduced Expression of O6-Methylguanine DNA Methyltransferase Is Associated With Helicobacter pylori Infection
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DOI：
10.1053/j.gastro.2009.12.042
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发表时间：
2010-05-01
期刊：
影响因子：
29.4
通讯作者：
Graham, David Y.
中科院分区：
文献类型：
--
作者：
Sepulveda, Antonia R.;Yao, Yuan;Graham, David Y.
背景与目的：幽门螺杆菌诱发胃炎期间，胃上皮细胞基因组发生了广泛的表观遗传改变。编码DNA修复蛋白o6 -甲基鸟嘌呤DNA甲基转移酶（MGMT）的基因在幽门螺杆菌胃炎患者中的表达可能通过其启动子的超甲基化而降低。我们通过CpG甲基化表征了幽门螺杆菌胃炎患者胃组织中MGMT的表达及其表观遗传调控，并研究了根除幽门螺杆菌感染对MGMT表达的影响。方法：采集幽门螺杆菌胃炎患者根除前后及幽门螺杆菌阴性对照者的胃活检标本。将AGS细胞与幽门螺杆菌共培养，研究幽门螺杆菌感染对MGMT RNA、蛋白表达和CpG甲基化的影响。结果：幽门螺杆菌胃炎患者胃黏膜MGMT CpG甲基化发生率（69.7%）高于无幽门螺杆菌胃炎患者（28.6%,P = 0.022）。幽门螺杆菌根除后，MGMT甲基化显著降低（从70%降至48%，P = 0.039）， CpG甲基化平均水平从12.6%降至5.7% (P = 0.025)， MGMT表达增加。MGMT甲基化与caga阳性幽门螺杆菌显著相关（P = 0.035）。幽门螺杆菌降低胃AGS细胞MGMT蛋白和RNA水平，诱导MGMT CpG甲基化。结论：幽门螺杆菌胃炎，特别是幽门螺杆菌caga阳性菌株感染的患者，与胃上皮MGMT高甲基化和MGMT水平降低有关。根除幽门螺杆菌感染后，MGMT启动子甲基化是部分可逆的。这些数据表明，DNA修复在幽门螺杆菌胃炎期间被破坏，增加了幽门螺杆菌感染胃粘膜的突变。
BACKGROUND & AIMS: The gastric epithelium genome undergoes extensive epigenetic alterations during Helicobacter pylori-induced gastritis. Expression of the gene encoding the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) might be reduced via hypermethylation of its promoter in patients with H pylori gastritis. We characterized expression of MGMT and its epigenetic regulation via CpG methylation in gastric tissue from patients with H pylori gastritis and investigated the effects of H pylori infection eradication on MGMT expression. METHODS: Gastric biopsy samples were collected from patients with H pylori gastritis before and after eradication and from H pylon-negative control subjects. AGS cells were cocultured with H pylori to study the effects of H pylori infection on MGMT RNA, protein expression, and CpG methylation. RESULTS: CpG methylation of MGMT was more frequent in the gastric mucosa of patients with H pylori gastritis (69.7%) than in those without (28.6%, P = .022). MGMT methylation was significantly reduced after H pylori eradication (from 70% to 48% of cases, P = .039), and mean levels of CpG methylation decreased from 12.6% to 5.7% (P = .025), increasing MGMT expression. MGMT methylation was significantly associated with CagA-positive H pylori (P = .035). H pylori reduced MGMT protein and RNA levels and induced MGMT CpG methylation in gastric AGS cells. CONCLUSIONS: H pylori gastritis, particularly in patients infected with H pylori CagA-positive strains, is associated with hypermethylation of MGMT and reduced levels of MGMT in the gastric epithelium. MGMT promoter methylation is partially reversible after eradication of H pylori infection. These data indicate that DNA repair is disrupted during H pylori gastritis, increasing mutagenesis in H pylori-infected gastric mucosa.