Analysis of A4gntKnockout Mice Reveals an Essential Role for Gastric Sulfomucins in Preventing Gastritis Cystica Profunda

Gastric adenocarcinoma cells secrete sulfomucins, but their role in gastric tumorigenesis remains unclear. To address that question, we generated A4gnt/Chst4double-knockout (DKO) mice by crossing A4gntknockout (KO) mice, which spontaneously develop gastric adenocarcinoma, with Chst4KO mice, which are deficient in the sulfotransferase GlcNAc6ST-2. A4gnt/Chst4DKO mice lack gastric sulfomucins but developed gastric adenocarcinoma. Unexpectedly, severe gastric erosion occurred in A4gnt/Chst4DKO mice at as early as 3 weeks of age, and with aging these lesions were accompanied by gastritis cystica profunda (GCP). Cxcl1, Cxcl5, Ccl2, and Cxcr2transcripts in gastric mucosa of 5-week-old A4gnt/Chst4DKO mice exhibiting both hyperplasia and severe erosion were significantly upregulated relative to age-matched A4gntKO mice, which showed hyperplasia alone. However, upregulation of these genes disappeared in 50-week-old A4gnt/Chst4DKO mice exhibiting high-grade dysplasia/adenocarcinoma and GCP. Moreover, Cxcl1and Cxcr2were downregulated in A4gnt/Chst4DKO mice relative to age-matched A4gntKO mice exhibiting adenocarcinoma alone. These combined results indicate that the presence of sulfomucins prevents severe gastric erosion followed by GCP in A4gntKO mice by transiently regulating a set of inflammation-related genes, Cxcl1, Cxcl5, Ccl2, and Cxcr2at 5 weeks of age, although sulfomucins were not directly associated with gastric cancer development: