Deficiency of Stomach-Type Claudin-18 in Mice Induces Gastric Tumor Formation Independent of H pylori InfectionSummary

Koya Suzuki; Kazuhiro Sentani; Hiroo Tanaka; Tomoki Yano; Kazuo Suzuki; Masanobu Oshima; Wataru Yasui; Atsushi Tamura; Sachiko Tsukita

Cellular and Molecular Gastroenterology and Hepatology (Jan 2019)

Deficiency of Stomach-Type Claudin-18 in Mice Induces Gastric Tumor Formation Independent of H pylori InfectionSummary

Koya Suzuki,
Kazuhiro Sentani,
Hiroo Tanaka,
Tomoki Yano,
Kazuo Suzuki,
Masanobu Oshima,
Wataru Yasui,
Atsushi Tamura,
Sachiko Tsukita

Affiliations

Koya Suzuki: Laboratory of Biological Science, Graduate School of Frontier Biosciences, and Graduate School of Medicine, Osaka University, Osaka, Japan; Research Institute for Diseases of Old Age and Department of Clinical Laboratory Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Koya Suzuki, Research Institute for Diseases of Old Age and Department of Clinical Laboratory Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan. fax: +81-3-5684-1609.
Kazuhiro Sentani: Department of Molecular Pathology, Hiroshima University, Institute of Biomedical and Health Sciences, Hiroshima, Japan
Hiroo Tanaka: Laboratory of Biological Science, Graduate School of Frontier Biosciences, and Graduate School of Medicine, Osaka University, Osaka, Japan
Tomoki Yano: Laboratory of Biological Science, Graduate School of Frontier Biosciences, and Graduate School of Medicine, Osaka University, Osaka, Japan
Kazuo Suzuki: Department of Health Protection, Graduate School of Medicine, Asia International Institute of Infectious Disease Control, Teikyo University, Tokyo, Japan
Masanobu Oshima: Division of Genetics, Cancer Research Institute, and Nano Life Science Institute, Kanazawa University, Kanazawa, Japan
Wataru Yasui: Department of Molecular Pathology, Hiroshima University, Institute of Biomedical and Health Sciences, Hiroshima, Japan
Atsushi Tamura: Laboratory of Biological Science, Graduate School of Frontier Biosciences, and Graduate School of Medicine, Osaka University, Osaka, Japan; Correspondence Address requests for reprints to: Atsushi Tamura, Laboratory of Biological Science, Graduate School of Frontier Biosciences, Osaka University, 2-2Yamadaoka, Suita, Osaka 565-0871, Japan. fax: +81-6-6879-3329.
Sachiko Tsukita: Laboratory of Biological Science, Graduate School of Frontier Biosciences, and Graduate School of Medicine, Osaka University, Osaka, Japan; Sachiko Tsukita, Laboratory of Biological Science, Graduate School of Frontier Biosciences, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. fax: +81-6-6879-3329.

Journal volume & issue: Vol. 8, no. 1
pp. 119 – 142

Abstract

Read online

Background & Aims: Epithelial cells are joined by tight junctions (TJs) to form a cell sheet. In the stomach, epithelial cell sheet forms an essential barrier against gastric material, including gastric acid. Although the decreased expression of stomach-type claudin-18 (stCldn18), a TJ protein, is generally observed in human gastritis and gastric cancer, its pathological roles are not fully understood. We previously reported that mice lacking stCldn18 (stCldn18-/-) exhibit gastric acid leakage through TJs, which induces active gastritis at a young age. Here, we examined the gastric pathologies in mice after long-term stCldn18 deficiency. Methods: The gastric pathologies in stCldn18-/- mice were sequentially analyzed from youth to old age, and compared to those in humans. To examine the relationship between stCldn18 deficiency-induced gastric pathologies and Wnt-dependent tumorigenesis, we generated Wnt1-overexpressing stCldn18-/- mice. Results: StCldn18-/- mice developed chronic active gastritis at middle age, with expression of the chemoattractant CCL28. At old age, 20-30% of these mice developed gastric tumors with CXCL5 expression, indicative of EMT. In this process, spasmolytic polypeptide-expressing metaplasia (SPEM) cells appeared. Increased expressions of CD44-variants, TLR2, and CXCL5 indicated age-dependent changes in cell characteristics. Some features of the stCldn18-/- mouse gastric tumorigenesis resembled H pylori-infection-related human carcinogenesis. The gastric tumorigenesis was accelerated in Wnt1-overexpressing stCldn18-/- mice, indicating that Wnt is involved in the stCldn18-/- mouse gastric tumorigenesis. Conclusions: StCldn18 deficiency induced gastric tumorigenesis in mice without H pylori infection. Our findings revealed that several signaling networks, including the cytokine-, stemness-, and Wnt-signaling pathways, may be activated under the stCldn18-deficiency-induced chronic active gastritis to accelerate the gastric tumorigenesis. Keywords: Epithelial Barrier, Tight Junction, Chronic Active Gastritis, SPEM

Published in Cellular and Molecular Gastroenterology and Hepatology

ISSN: 2352-345X (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.journals.elsevier.com/cellular-and-molecular-gastroenterology-and-hepatology/

About the journal