Core 1–derived mucin-type O-glycans (O-glycans) are a major component of gastric mucus with an unclear role. To address this, we generated mice lacking gastric epithelial O-glycans (GEC C1galt1−/−). GEC C1galt1−/− mice exhibited spontaneous gastritis that progressed to adenocarcinoma with ∼80% penetrance by 1 yr. GEC C1galt1−/− gastric epithelium exhibited defective expression of a major mucus forming O-glycoprotein Muc5AC relative to WT controls, which was associated with impaired gastric acid homeostasis. Inflammation and tumorigenesis in GEC C1galt1−/− stomach were concurrent with activation of caspases 1 and 11 (Casp1/11)–dependent inflammasome. GEC C1galt1−/− mice genetically lacking Casp1/11 had reduced gastritis and gastric cancer progression. Notably, expression of Tn antigen, a truncated form of O-glycan, and CASP1 activation was associated with tumor progression in gastric cancer patients. These results reveal a critical role of O-glycosylation in gastric homeostasis and the protection of the gastric mucosa from Casp1-mediated gastric inflammation and cancer.
Core 1–derived mucin-type O-glycosylation protects against spontaneous gastritis and gastric cancer
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Fei Liu, Jianxin Fu, Kirk Bergstrom, Xindi Shan, J. Michael McDaniel, Samuel McGee, Xia Bai, Weichang Chen, Lijun Xia; Core 1–derived mucin-type O-glycosylation protects against spontaneous gastritis and gastric cancer. J Exp Med 6 January 2020; 217 (1): e20182325. doi: https://doi.org/10.1084/jem.20182325
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