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

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 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.

Unraveling a New Role for Claudins in Gastric Tumorigenesis

“…In the current issue of Cellular and Molecular Gastroenterology and Hepatology , a study by Suzuki et al 8 added another important piece to the puzzle. They dissected pathways regulating the transition to metaplasia and then tumor development in young (8 weeks after birth), middle-aged (40 weeks after birth), and aged (>60 weeks after birth) st Cldn18 -KO mice.…”

“…They dissected pathways regulating the transition to metaplasia and then tumor development in young (8 weeks after birth), middle-aged (40 weeks after birth), and aged (>60 weeks after birth) st Cldn18 -KO mice. Suzuki et al 8 found that active gastritis in young st Cldn18 -KO mice became chronic active gastritis by the time the mice were middle aged. This transition was accompanied by altered cytokine profiles and increased signal transducer and activator of transcription 3 and nuclear factor-κB signaling.…”

<p>Curcumin Modifies Epithelial–Mesenchymal Transition in Colorectal Cancer Through Regulation of miR-200c/EPM5</p>

“…EMT is considered as a response to the combination of extracellular signaling, in which a number of molecules were involved, such as microRNA family. 28,29 To address whether the curcumin-repressed EMT was due to the upregulation of tumor-suppressive miRNAs, a miRNA array containing 90 miRNAs was performed. Therefore, three miRNAs were upregulated, whereas one miRNA was downregulated in SW620 cells after curcumin treatment (Figure 2A-C).…”

Syzygium aromaticum L.: Traditional herbal medicine against cagA and vacA toxin genes-producing drug resistant Helicobacter pylori

“…Helicobacter pylori ( H. pylori ) infection is a well-known risk factor for human gastritis, gastric cancer and inflammation-associated diseases. 1 , 2 , 3 Gastric cancer is a model for inflammation-induced cancer, which is recognized as the third most common cause of cancer related death worldwide. 4 H. pylori which has been christened as a class 1 carcinogen by the World Health Organization (WHO), acquired the shape of an epidemic emerging as a principle cause of gastric carcinoma.…”