Analysis of A4gnt Knockout Mice Reveals an Essential Role for Gastric Sulfomucins in Preventing Gastritis Cystica Profunda. (October 2019)

• Record Type: Journal Article
• Authors: Kawakubo, Masatomo; Komura, Hitomi; Goso, Yukinobu; Okumura, Motohiro; Sato, Yoshiko; Fujii, Chifumi; Miyashita, Masaki; Arisaka, Nobuhiko; Harumiya, Satoru; Yamanoi, Kazuhiro; Yamada, Shigenori; Kakuta, Shigeru; Kawashima, Hiroto; Fukuda, Michiko N.; Fukuda, Minoru; Nakayama, Jun
• Is Part Of: Journal of histochemistry and cytochemistry. Volume 67:Number 10(2019:Oct.)
• Page Start: 759
• Page End: 770
• Publication Date: 2019-10
• Subjects: A4gnt -- Chst4 -- double knockout mouse -- gastritis cystica profunda -- gastric mucin -- O-glycan; Histochemistry -- Periodicals; Cytochemistry -- Periodicals; Histocytochemistry -- methods; Histological Techniques; 572.05
• DOI: 10.1369/0022155419860134
• Languages: English
• ISSNs: 0022-1554

Abstract

Gastric adenocarcinoma cells secrete sulfomucins, but their role in gastric tumorigenesis remains unclear. To address that question, we generated A4gnt / Chst4 double-knockout (DKO) mice by crossing A4gnt knockout (KO) mice, which spontaneously develop gastric adenocarcinoma, with Chst4 KO mice, which are deficient in the sulfotransferase GlcNAc6ST-2. A4gnt / Chst4 DKO mice lack gastric sulfomucins but developed gastric adenocarcinoma. Unexpectedly, severe gastric erosion occurred in A4gnt / Chst4 DKO 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 Cxcr2 transcripts in gastric mucosa of 5-week-old A4gnt / Chst4 DKO mice exhibiting both hyperplasia and severe erosion were significantly upregulated relative to age-matched A4gnt KO mice, which showed hyperplasia alone. However, upregulation of these genes disappeared in 50-week-old A4gnt / Chst4 DKO mice exhibiting high-grade dysplasia/adenocarcinoma and GCP. Moreover, Cxcl1 and Cxcr2 were downregulated in A4gnt / Chst4 DKO mice relative to age-matched A4gnt KO mice exhibiting adenocarcinoma alone. These combined results indicate that the presence of sulfomucins prevents severe gastric erosion followed by GCP in A4gnt KO mice by transiently regulating a set of inflammation-related genes, Cxcl1, Cxcl5, Ccl2, and Cxcr2 at 5 weeks of age, although sulfomucins were not directly associated with gastric cancer development: