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核心 1 衍生的粘蛋白型 O-糖基化可预防自发性胃炎和胃癌。

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

机构信息

Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.

Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK.

出版信息

J Exp Med. 2020 Jan 6;217(1). doi: 10.1084/jem.20182325.

DOI:10.1084/jem.20182325
PMID:31645367
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7037257/
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.

摘要

核心 1 衍生的粘蛋白型 O-聚糖 (O-聚糖) 是胃粘液的主要成分，其作用尚不清楚。为了解决这个问题，我们生成了缺乏胃上皮 O-聚糖的小鼠 (GEC C1galt1-/-)。GEC C1galt1-/-小鼠表现出自发性胃炎，在 1 年内进展为腺癌，其外显率约为 80%。与 WT 对照相比，GEC C1galt1-/-胃上皮细胞中主要的粘液形成 O-糖蛋白 Muc5AC 的表达缺陷，这与胃胃酸稳态受损有关。GEC C1galt1-/-胃中的炎症和肿瘤发生与 Caspase 1 和 11 (Casp1/11) 依赖性炎性体的激活同时发生。在遗传上缺乏 Casp1/11 的 GEC C1galt1-/-小鼠中，胃炎和胃癌的进展减少。值得注意的是，Tn 抗原的表达，一种 O-聚糖的截断形式，以及 CASP1 的激活与胃癌患者的肿瘤进展相关。这些结果揭示了 O-糖基化在胃稳态中的关键作用，以及它对胃粘膜免受 Casp1 介导的胃炎症和癌症的保护作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/9a270ffe9087/JEM_20182325_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/e20192cacf3c/JEM_20182325_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/708785da23da/JEM_20182325_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/c77934c5aeef/JEM_20182325_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/64cce0394b11/JEM_20182325_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/1b83d1d2b659/JEM_20182325_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/dc6722f9ed93/JEM_20182325_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/ce95d8772b52/JEM_20182325_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/925d07126071/JEM_20182325_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/52dc92c9e17d/JEM_20182325_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/7f6b7fd27cc9/JEM_20182325_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/3cf59aeb0240/JEM_20182325_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/9a270ffe9087/JEM_20182325_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/e20192cacf3c/JEM_20182325_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/708785da23da/JEM_20182325_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/c77934c5aeef/JEM_20182325_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/64cce0394b11/JEM_20182325_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/1b83d1d2b659/JEM_20182325_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/dc6722f9ed93/JEM_20182325_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/ce95d8772b52/JEM_20182325_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/925d07126071/JEM_20182325_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/52dc92c9e17d/JEM_20182325_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/7f6b7fd27cc9/JEM_20182325_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/3cf59aeb0240/JEM_20182325_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4ae2/7037257/9a270ffe9087/JEM_20182325_Fig8.jpg

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