Epigenetic downregulation of MUC17 by H. pylori infection facilitates NF-κB-mediated expression of CEACAM1-3S in human gastric cancer
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.
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.
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.
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.
KeywordsH. pylori Mucin 17 CEACAM1 CagA Gastric cancer
This work was supported by grants from National Natural Science Foundation of China (Grant nos. 81872021, 81572346, 81772502), Natural Science Foundation of Beijing Municipality (Grant no. 7182027), National Key Research and Development Program of China (2017YFC1308900), Beijing Municipal Commission of Health and Family Planning Project (PXM2018_026279_000005), National Bio-Tech 863 Program (no. 2012AA02A203), Beijing Nova Program (Z151100000315069), Beijing Talent Fund, and Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (ZYLX201701). And we also thank the tissue bank of Peking University Cancer Hospital/Institute for providing gastric specimens.
Compliance with ethical standards
Conflict of interest
None of the authors have conflicts of interest that could potentially influence.
This study was conducted with the approval of the Institutional Ethical Standards Committee.
Human rights statement and informed consent
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study.
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