Essential role of gastric gland mucin in preventing gastric cancer in mice.

ABSTRACT: Gastric gland mucin secreted from the lower portion of the gastric mucosa contains unique O-linked oligosaccharides (O-glycans) having terminal ?1,4-linked N-acetylglucosamine residues (?GlcNAc). Previously, we identified human ?1,4-N-acetylglucosaminyltransferase (?4GnT), which is responsible for the O-glycan biosynthesis and characterized ?GlcNAc function in suppressing Helicobacter pylori in vitro. In the present study, we engineered A4gnt(-/-) mice to better understand its role in vivo. A4gnt(-/-) mice showed complete lack of ?GlcNAc expression in gastric gland mucin. Surprisingly, all the mutant mice developed gastric adenocarcinoma through a hyperplasia-dysplasia-carcinoma sequence in the absence of H. pylori infection. Microarray and quantitative RT-PCR analysis revealed upregulation of genes encoding inflammatory chemokine ligands, proinflammatory cytokines, and growth factors, such as Ccl2, Il-11, and Hgf in the gastric mucosa of A4gnt(-/-) mice. Further supporting an important role for this O-glycan in cancer progression, we also observed significantly reduced ?GlcNAc in human gastric adenocarcinoma and adenoma. Our results demonstrate that the absence of ?GlcNAc triggers gastric tumorigenesis through inflammation-associated pathways in vivo. Thus, ?GlcNAc-terminated gastric mucin plays dual roles in preventing gastric cancer by inhibiting H. pylori infection and also suppressing tumor-promoting inflammation.

SUBMITTER: Karasawa F 

PROVIDER: S-EPMC3287219 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature