Core 1-derived mucin-type O-glycosylation protects against spontaneous gastritis and gastric cancer
Core 1-derived mucin-type O-glycosylation protects against spontaneous gastritis and gastric cancer
复制标题
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
DOI：
10.1084/jem.20182325
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发表时间：
2020-01-01
影响因子：
15.3
通讯作者：
Xia, Lijun
中科院分区：
文献类型：
--
作者：
Liu, Fei;Fu, Jianxin;Xia, Lijun
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，作用尚不清楚。为了解决这个问题，我们产生了缺乏胃上皮O-聚糖（GEC C1 galt 1（-/-））的小鼠。GEC C1 galt 1（-/-）小鼠表现出自发性胃炎，进展为腺癌，1年时的复发率接近80%。相对于WT对照，GEC C1 galt 1（-/-）胃上皮表现出主要粘液形成O-糖蛋白Muc 5AC的表达缺陷，这与胃酸稳态受损相关。GEC C1 galt 1（-/-）胃中的炎症和肿瘤发生与Caspases 1和11（Casp 1/11）依赖性炎性体的激活同时发生。GEC C1 galt 1（-/-）小鼠基因缺乏Casp 1/11减少胃炎和胃癌进展。值得注意的是，Tn抗原（O-聚糖的截短形式）的表达和CASP 1活化与胃癌患者的肿瘤进展相关。这些结果揭示了O-糖基化在胃内环境稳定和保护胃粘膜免受Casp 1介导的胃炎症和癌症中的关键作用。
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 similar to 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.