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

Author:

Liu Fei12,Fu Jianxin2,Bergstrom Kirk2,Shan Xindi2,McDaniel J. Michael2,McGee Samuel2,Bai Xia34,Chen Weichang1,Xia Lijun235ORCID

Affiliation:

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 Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK

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.

Funder

China Scholarship Council

Jiangsu Provincial Natural Science Foundation

Jiangsu Provincial Special Program of Medical Science

Jiangsu Provincial Key Medical Center

Jiangsu Higher Education Institutions

Oklahoma Center for Adult Stem Cell Research

Oklahoma Medical Research Foundation

National Natural Science Foundation of China

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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