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J Exp Med. 2019 Oct 23. pii: jem.20182325. doi: 10.1084/jem.20182325. [Epub ahead of print]

Core 1-derived mucin-type O-glycosylation protects against spontaneous gastritis and gastric cancer.

Author information

1
Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
2
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK.
3
Jiangsu Institute of Hematology, Collaborative Innovation Center of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
4
State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China.
5
Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China weichangchen@126.com.
6
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK lijun-xia@omrf.org weichangchen@126.com.
7
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
#
Contributed equally

Abstract

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.

PMID:
31645367
DOI:
10.1084/jem.20182325

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