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

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.

Tn Antigen Expression Contributes to an Immune Suppressive Microenvironment and Drives Tumor Growth in Colorectal Cancer

“…Overexpression of Tn antigen has been shown to promote tumor growth in CRC (11,51) and pancreatic cancer (13). Moreover, in some models the mere abrogation of T-synthase/COSMC is sufficient to induce oncogenic features and to augment tumorigenesis of otherwise healthy cells (12,52). In contrast, enhanced T antigen expression also correlates to bad prognosis and oncogenesis in, for instance, breast (31,53,54) and head and neck cancer (55).…”

Integrative Analysis of MUC4 to Prognosis and Immune Infiltration in Pan-Cancer: Friend or Foe?

“…Past research has shown the critical roles of mucins in tumorigenesis (van Putten and Strijbis, 2017;Maeda et al, 2018;Ganguly et al, 2020;Liu et al, 2020), which indicated their prospective usefulness in cancer diagnosis, prognosis, and therapy (Nabavinia et al, 2017;Aithal et al, 2018;Guo et al, 2018;Lucchetta et al, 2019;Pothuraju et al, 2020). Previous studies have raised hope that MUC4 can be a good candidate marker for pancreatic malignancy (Trabbic et al, 2019;Gautam et al, 2020).…”

C1GALT1 in health and disease (Review)

“…C1GALT1 has been shown to be a tumor suppressor gene in pancreatic cancer since the absence of C1GALT1 expression promotes the development and metastasis of pancreatic cancer ( 30 ). However, in another study, C1GALT1 served a different role ( 31 ). Liu et al ( 31 ) found that in C1GALT1 -knockout mice, spontaneous gastroenteritis and consequently gastric antral adenocarcinoma were improved in the gastric mucosal epithelial cells, which indicates that C1GALT1 -mediated O -glycosylation is very important for gastric mucosal and gastric homeostasis protection ( 31 ).…”

“…However, in another study, C1GALT1 served a different role ( 31 ). Liu et al ( 31 ) found that in C1GALT1 -knockout mice, spontaneous gastroenteritis and consequently gastric antral adenocarcinoma were improved in the gastric mucosal epithelial cells, which indicates that C1GALT1 -mediated O -glycosylation is very important for gastric mucosal and gastric homeostasis protection ( 31 ). However, the use of samples from different sources or at different tumor stages may have contributed to the observed dual function of C1GALT1 ; hence, the true role of the gene remains elusive.…”