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

Introduction Gel-forming mucins covering the gastric mucosa are heavily glycosylated glycoproteins that form a barrier between the stomach and the external environment. Gastric mucins are divided into surface mucin and [...]
Gastric gland mucin secreted from the lower portion of the gastric mucosa contains unique O-linked oligosaccharides (O-glycans) having terminal α 1,4-linked N-acetylglucosamine residues (α GlcNAc). Previously, we identified human α 1,4-N-acetylglucosaminyltransferase (α 4GnT), which is responsible for the O-glycan biosynthesis and characterized α GlcNAc function in suppressing Helicobacter pylori in vitro. In the present study, we engineered [A4gnt.sup.-/-] mice to better understand its role in vivo. [A4gnt.sup.-/-] mice showed complete lack of α 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.sup.-/-] mice. Further supporting an important role for this O-glycan in cancer progression, we also observed significantly reduced α GlcNAc in human gastric adenocarcinoma and adenoma. Our results demonstrate that the absence of α GlcNAc triggers gastric tumorigenesis through inflammation-associated pathways in vivo. Thus, α GlcNAc-terminated gastric mucin plays dual roles in preventing gastric cancer by inhibiting H. pylori infection and also suppressing tumor-promoting inflammation.