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 s
tCldn18-/-
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 s
tCldn18-/-
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.