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

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

doi:10.1016/j.jcmgh.2019.03.003

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

Cell Mol Gastroenterol Hepatol. 2019;8(1):119-142. doi: 10.1016/j.jcmgh.2019.03.003. Epub 2019 Mar 23.

Authors

Koya Suzuki¹, Kazuhiro Sentani², Hiroo Tanaka³, Tomoki Yano³, Kazuo Suzuki⁴, Masanobu Oshima⁵, Wataru Yasui², Atsushi Tamura⁶, Sachiko Tsukita⁷

Affiliations

¹ 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. Electronic address: [email protected].
² Department of Molecular Pathology, Hiroshima University, Institute of Biomedical and Health Sciences, Hiroshima, Japan.
³ Laboratory of Biological Science, Graduate School of Frontier Biosciences, and Graduate School of Medicine, Osaka University, Osaka, Japan.
⁴ Department of Health Protection, Graduate School of Medicine, Asia International Institute of Infectious Disease Control, Teikyo University, Tokyo, Japan.
⁵ Division of Genetics, Cancer Research Institute, and Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.
⁶ Laboratory of Biological Science, Graduate School of Frontier Biosciences, and Graduate School of Medicine, Osaka University, Osaka, Japan. Electronic address: [email protected].
⁷ Laboratory of Biological Science, Graduate School of Frontier Biosciences, and Graduate School of Medicine, Osaka University, Osaka, Japan. Electronic address: [email protected].

Abstract

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: Chronic Active Gastritis; Epithelial Barrier; SPEM; Tight Junction.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Claudins / deficiency*
Cytokines / genetics
Disease Models, Animal
Disease Progression
Gastritis / genetics
Gastritis / pathology*
Humans
Mice
Signal Transduction
Stomach Neoplasms / genetics
Stomach Neoplasms / pathology*
Wnt Signaling Pathway
Wnt1 Protein / genetics

Substances

Claudins
Cldn18 protein, mouse
Cytokines
Wnt1 Protein
Wnt1 protein, mouse