Institut Pasteur, Unité de Pathogenèse de Helicobacter, Paris, France.
Cell Microbiol. 2010 Aug;12(8):1124-33. doi: 10.1111/j.1462-5822.2010.01457.x. Epub 2010 Feb 23.
Helicobacter pylori infection is associated with the development of gastric adenocarcinoma. Upstream stimulatory factors USF1 and USF2 regulate the transcription of genes related to immune response, cell cycle and cell proliferation. A decrease in their expression is observed in human gastric epithelial cells infected with H. pylori, associated to a lower binding to their DNA E-box recognition site as shown by electrophoretic mobility shift assay. DNA methylation leads to gene silencing. The treatment of cells with 5'-azacytidine, an inhibitor of DNA methylation, restored the USF1 and USF2 gene expression in the presence of infection. Using promoter PCR methylation assay, a DNA hypermethylation was shown in the promoter region of USF1 and USF2 genes, in infected cells. The inhibition of USF1 and USF2 expression by H. pylori and the DNA hypermethylation in their gene promoter region was confirmed in gastric tissues isolated from 12 to 18 months infected mice. Our study demonstrated the involvement of USF1 and USF2 as molecular targets of H. pylori and the key role of DNA methylation in their regulation. These mechanisms occurred in the context of metaplastic lesions, suggesting that alteration of USF1 and USF2 levels could participate in the promotion of neoplastic process during H. pylori infection.
幽门螺杆菌感染与胃腺癌的发展有关。上游刺激因子 USF1 和 USF2 调节与免疫反应、细胞周期和细胞增殖相关基因的转录。在幽门螺杆菌感染的人类胃上皮细胞中观察到它们的表达减少，这与电泳迁移率变动分析所示的与它们的 DNA E 盒识别位点的结合降低有关。DNA 甲基化导致基因沉默。用 5'-氮杂胞苷（一种 DNA 甲基化抑制剂）处理细胞，在感染存在的情况下恢复了 USF1 和 USF2 基因的表达。使用启动子 PCR 甲基化测定法，在感染细胞的 USF1 和 USF2 基因启动子区域显示出 DNA 高甲基化。在从感染 12 至 18 个月的小鼠分离的胃组织中证实了幽门螺杆菌对 USF1 和 USF2 表达的抑制以及其基因启动子区域的 DNA 高甲基化。我们的研究表明 USF1 和 USF2 作为幽门螺杆菌的分子靶标以及 DNA 甲基化在其调节中的关键作用。这些机制发生在化生病变的背景下，表明 USF1 和 USF2 水平的改变可能参与了幽门螺杆菌感染过程中肿瘤发生过程的促进。
