Analysis of A4gnt Knockout Mice Reveals an Essential Role for Gastric Sulfomucins in Preventing Gastritis Cystica Profunda

Masatomo Kawakubo, Hitomi Komura, Yukinobu Goso, Motohiro Okumura, Yoshiko Sato, Chifumi Fujii, Masaki Miyashita, Nobuhiko Arisaka, Satoru Harumiya, Kazuhiro Yamanoi, Shigenori Yamada, Shigeru Kakuta, Hiroto Kawashima, Michiko N. Fukuda, Minoru Fukuda, Jun Nakayama

Research output: Contribution to journalArticle

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:.

Original languageEnglish
Pages (from-to)759-770
Number of pages12
JournalJournal of Histochemistry and Cytochemistry
Volume67
Issue number10
DOIs
Publication statusPublished - 2019 Oct 1

Keywords

  • A4gnt
  • Chst4
  • O-glycan
  • double knockout mouse
  • gastric mucin
  • gastritis cystica profunda

ASJC Scopus subject areas

  • Anatomy
  • Histology

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    Kawakubo, M., Komura, H., Goso, Y., Okumura, M., Sato, Y., Fujii, C., Miyashita, M., Arisaka, N., Harumiya, S., Yamanoi, K., Yamada, S., Kakuta, S., Kawashima, H., Fukuda, M. N., Fukuda, M., & Nakayama, J. (2019). Analysis of A4gnt Knockout Mice Reveals an Essential Role for Gastric Sulfomucins in Preventing Gastritis Cystica Profunda. Journal of Histochemistry and Cytochemistry, 67(10), 759-770. https://doi.org/10.1369/0022155419860134