幽门螺杆菌感染通过表观遗传下调 MUC17 促进 NF-κB 介导的人类胃癌中 CEACAM1-3S 的表达。
Epigenetic downregulation of MUC17 by H. pylori infection facilitates NF-κB-mediated expression of CEACAM1-3S in human gastric cancer.
机构信息
Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, 100142, People's Republic of China.
College of Life Sciences and Bioengineering, School of Science, Beijing Jiaotong University, 3 Shangyuancun, Haidian District, Beijing, 100044, People's Republic of China.
出版信息
Gastric Cancer. 2019 Sep;22(5):941-954. doi: 10.1007/s10120-019-00932-0. Epub 2019 Feb 18.
BACKGROUND AND AIMS
Helicobacter pylori invades the mucosal barrier and infects the mucins of gastric epithelial cells. However, whether gastric carcinogenesis caused by H. pylori infection involves the membrane-bound mucins is unclear. This study explored the role of mucin 17 (MUC17) in gastric cancer (GC) associated with H. pylori infection.
METHODS
The expression of MUC17 and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) was examined in human GC cells and tissues with H. pylori infection. Gain- and loss-of-function assays were performed to assess the role of MUC17 in regulating CEACAM1 in H. pylori-infected GC cells.
RESULTS
MUC17 was downregulated in H. pylori-infected GC cells and tissues in association with poor survival of GC patients. Downregulation of MUC17 was attributable to MUC17 promoter methylation mediated by DNA methyltransferase 1 (DNMT1) H. pylori-enhanced GC cell proliferation and colony formation associated with MUC17 downregulation. Gain- and loss-of-function assays showed that MUC17 inhibited the H. pylori-enhanced GC cell growth by preventing the translocation of H. pylori CagA into GC cells. Moreover, MUC17 downregulated the expression of CEACAM1 variant 3S (CEACAM1-3S) in GC cells and tissues with H. pylori infection. Additionally, MUC17 downregulated CEACAM1 promoter activity via attenuation of NF-κB activation in GC cells.
CONCLUSIONS
MUC17 was epigenetically downregulated in GC with H. pylori infection. MUC17 inhibited H. pylori CagA translocation via attenuation of NF-κB-mediated expression of CEACAM1-3S in GC cells. Thus, MUC17 may serve as a valuable prognostic biomarker for H. pylori-associated GC.
背景与目的
幽门螺杆菌（H. pylori）侵袭黏膜屏障并感染胃上皮细胞的黏蛋白。然而，H. pylori 感染引起的胃癌（GC）是否涉及膜结合黏蛋白尚不清楚。本研究探讨了黏蛋白 17（MUC17）在与 H. pylori 感染相关的 GC 中的作用。
方法
检测人 GC 细胞和组织中 MUC17 和癌胚抗原相关细胞黏附分子 1（CEACAM1）的表达，通过 gain-和 loss-of-function 实验评估 MUC17 在调节 H. pylori 感染 GC 细胞中 CEACAM1 的作用。
结果
在 H. pylori 感染的 GC 细胞和组织中，MUC17 表达下调，与 GC 患者生存不良相关。MUC17 下调归因于 DNA 甲基转移酶 1（DNMT1）介导的 MUC17 启动子甲基化。H. pylori 增强 GC 细胞增殖和集落形成与 MUC17 下调有关。Gain-和 loss-of-function 实验表明，MUC17 通过阻止 H. pylori CagA 进入 GC 细胞，抑制 H. pylori 增强的 GC 细胞生长。此外，MUC17 下调了 H. pylori 感染的 GC 细胞和组织中 CEACAM1 变体 3S（CEACAM1-3S）的表达。此外，MUC17 通过减弱 NF-κB 激活来下调 GC 细胞中 CEACAM1 启动子活性。
结论
在 H. pylori 感染的 GC 中，MUC17 被表观遗传下调。MUC17 通过减弱 NF-κB 介导的 CEACAM1-3S 表达来抑制 H. pylori CagA 易位。因此，MUC17 可能作为 H. pylori 相关 GC 的有价值的预后生物标志物。
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