Department of Pathology and Lab Medicine, All India Institute of Medical Sciences, Bhubaneswar, India.
Department of Gastroenterology, All India Institute of Medical Sciences, Bhubaneswar, India.
Dig Dis. 2022;40(2):156-167. doi: 10.1159/000516478. Epub 2021 Apr 23.
The aim of this study was to study the role of key epigenetic regulators pertaining to DNA methylation and histone-modification systems in Helicobacter pylori (HP)-associated gastritis and gastric carcinogenesis.
The expression of DNA methyltransferase (DNMT-1, 3A, and 3B) and the catalytic subunit of polycomb repressive complex-2 (enhancer of zeste homolog 2 [EZH2]) in gastric carcinomas (n = 104), mucosa adjacent to carcinoma (n = 104), HP-associated gastritis (n = 95), and histologically normal mucosa (n = 31) was assessed by immunohistochemistry and qRT-PCR.
The expression of all 3 DNMTs and EZH2 was significantly higher in HP-associated gastritis and carcinoma cases than in those with adjacent and normal mucosa. The expression of DNMT-1 and 3B was maximum in HP-associated gastritis. DNMT-3A showed higher expression in carcinoma-adjacent mucosa than in normal mucosa. Interestingly, the expression of EZH2 was higher in cases of HP-associated gastritis with metaplasia than in those without metaplasia and also in cases of intestinal type of adenocarcinoma. Significant positive correlation of EZH2 was identified with DNMT-1, DNMT-3A, and DNMT-3B. However, none of these markers was associated with survival outcome.
This study establishes an important role of the key epigenetic regulators in the pathogenesis of both HP-associated gastritis and gastric carcinoma. Higher expression of all the epigenetic markers in the gastritis and their persistence in the carcinoma point toward their implications in HP-driven gastric carcinogenesis. Further, an inter-relation between the 2 arms of epigenetics, namely, DNA methylation and histone-modification in the pathogenesis of gastric carcinoma, is also documented. Given the reversibility of epigenetic phenomenon, these molecules may be of important therapeutic use.
本研究旨在探讨与 DNA 甲基化和组蛋白修饰系统相关的关键表观遗传调控因子在幽门螺杆菌（HP）相关胃炎和胃癌发生中的作用。
采用免疫组织化学和 qRT-PCR 方法检测 104 例胃癌、癌旁组织（n=104）、HP 相关胃炎（n=95）和组织学正常黏膜（n=31）中 DNA 甲基转移酶（DNMT-1、3A 和 3B）和多梳抑制复合物 2 的催化亚基（增强子的锌指蛋白 2 [EZH2]）的表达。
在 HP 相关胃炎和癌组织中，所有 3 种 DNMT 和 EZH2 的表达均明显高于癌旁和正常黏膜组织。DNMT-1 和 3B 在 HP 相关胃炎中表达最高。DNMT-3A 在癌旁黏膜中的表达高于正常黏膜。有趣的是，在伴有化生的 HP 相关胃炎中，EZH2 的表达高于无化生者，在肠型腺癌中也如此。EZH2 与 DNMT-1、DNMT-3A 和 DNMT-3B 呈显著正相关。然而，这些标志物均与生存结局无关。
本研究确立了关键表观遗传调控因子在 HP 相关胃炎和胃癌发病机制中的重要作用。这些表观遗传标志物在胃炎中的高表达及其在癌组织中的持续存在提示其在 HP 驱动的胃癌发生中的作用。此外，还记录了表观遗传学的 2 个分支，即 DNA 甲基化和组蛋白修饰在胃癌发病机制中的相互关系。鉴于表观遗传现象的可逆性，这些分子可能具有重要的治疗用途。
