Loss of Tight Junction Protein Claudin 18 Promotes Progressive Neoplasia Development in Mouse Stomach

Hagen, Susan J.; Ang, Lay‐Hong; Zheng, Yi; Karahan, Salih Nafiz; Wu, Jessica L.; Wang, Yaoyu E.; Caron, Tyler; Gad, Aniket; Muthupalani, Sureshkumar; Fox, James G.

doi:10.1053/j.gastro.2018.08.041

Cited by 78 publications

(95 citation statements)

References 66 publications

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“…To date, little is known about the clinical impact of CLDN18.2 expression in metastatic GC. Previous studies have suggested that loss of CLDN18.2 expression is associated with an increased proliferative and invasive potential of GC [21,22]. We found that CLDN18.2 and E-cadherin expression was decreased in patients with PM compared to those without PM.…”

Section: Discussionsupporting

confidence: 45%

Clinical Significance of CLDN18.2 Expression in Diffuse-Type Metastatic Gastric Cancer

Kim

Shin

Park

et al. 2020

Preprint

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Background Isoform 2 of the tight junction protein claudin-18 (CLDN18.2) is a potential target of gastric cancer treatment. A treatment targeting CLDN18.2 has shown promising results in gastric cancer. We investigated the clinical significance of CLDN18.2 and other cell-adherens junction molecules (Rho GTPase-activating protein [RhoGAP] and E-cadherin) in metastatic diffuse-type gastric cancer (mDGC).Methods We evaluated CLDN18.2, RhoGAP, and E-cadherin expression by performing two-plex immunofluorescence and quantitative data analysis of H-scores of 77 consecutive mDGC patients who received first-line, platinum-based chemotherapy between March 2015 and February 2017.Results CLDN18.2 and E-cadherin expression was significantly reduced in patients with peritoneal metastasis (PM) compared with those without PM at the time of diagnosis (P=0.010 and 0.013, respectively), while it was significantly higher in patients who never exhibited PM from diagnosis to death than in those who did (p=0.001 and 0.003, respectively). Meanwhile, CLDN18.2 and E-cadherin were expressed at significantly higher levels in patients with bone metastasis than in those without it (p=0.010 and 0.001, respectively). We identified a positive correlation between the expression of CLDN18.2 and E-cadherin (p < 0.001), RhoGAP and CLDN18.2 (p=0.004), and RhoGAP and E-cadherin (p=0.001). CDLN18.2, RhoGAP, and E-cadherin expression was not associated with chemotherapy response and survival.Conclusions CLDN18.2 expression was reduced in PM but significantly intact in bone metastasis. Furthermore, a positive correlation was identified between the expression of CLDN18.2 and other adherens junction molecules, which has clinical implications for mDGC and PM pathogenesis.

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Section: Discussionsupporting

confidence: 45%

Clinical Significance of CLDN18.2 Expression in Diffuse-Type Metastatic Gastric Cancer

Kim

Shin

Park

et al. 2020

Preprint

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“…Moreover, IM was confirmed by overexpression of MUC2, and by finding Alcian blue/Periodic Acid-Schiff-stained cells at the surface and base of gland ( Figure 3E). These results demonstrated that Slc26a9 KM aged 6 months exhibited robust expression levels of the markers for chronic atrophic gastric, metaplasia, mucosal barrier defect and dysplasia that were also found in human GC [12]. Based on gene microarray analyses, known oncogenes in GC, including ErbB2, Cdkn2a, MAX, TERT, K-Ras, N-Ras, Cyclin E, c-Met and FGFR2, were upregulated at 14 months of age, whereas tumor suppressors, P53, CDH1, and APC, were downregulated ( Figure 3A).…”

Section: Identification Of Molecular Markers For Atrophy Spem Im Mmentioning

confidence: 60%

“…Furthermore, Slc26a9 deletion leaded to the alteration of multiple signaling pathways that are related to the regulation of cell proliferation, apoptosis, and differentiation, as well as barrier integrity. Emerging evidence suggests that activation of Wnt signaling pathway can be linked to GC development and progression [12,38]. Activation of the Wnt pathway is known to result in β-catenin nuclear accumulation [24].…”

Section: Discussionmentioning

confidence: 99%

Parietal cell-Specific SLC26A9 Deletion induces spontaneous Gastric Carcinogenesis in Mice

Liu

Yuan³

et al. 2020

Preprint

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Previous study showed that Slc26a9 loss impairs parietal cell function and survival. We investigated whether Slc26a9 loss causes spontaneous gastric carcinogenesis in mice and plays a role in the development and progression in human gastric cancer (GC). Gastric histopathology and potential molecular mechanism were explored in Slc26a9 knockout mice and wild-type littermates as well as Slc26a9fl/fl/Atp4b-Cre and Slc26a9fl/fl mice from 8 days to 18 months by histological and immunohistochemical analyses, quantitative PCR, in situ hybridization, and RNA microarray analysis, respectively. We demonstrated that loss of parietal cell expression of Slc26a9 is the key event to induce spontaneous gastric carcinogenesis in mice, and clarified the sequence of events leading to malignant transformation, including Slc26a9 deficiency in parietal cells resulted in dysregulated differentiation of stem cells in an inflammatory environment, activated Wnt signaling pathway to induce gastric epithelia cell hyperproliferation and apoptosis inhibition, as well as spontaneous epithelial to mesenchymal transition-induced cancer stem cell phenotypes. Downregulation of SLC26A9 correlated with GC patient’s short survival.Graphical AbstractLoss of parietal cell expression of Slc26a9 is the key event to induce spontaneous gastric carcinogenesis in transgenic mice.

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“…Loss of epithelial integrity by disruption of cell‐cell junctions mediated by H pylori may also contribute to gastric carcinogenesis. Hagen et al showed that H pylori infection induces attenuation/loss of the tight junction protein Claudin‐18 in the stomach of mice. Deletion of Claudin‐18 in these animals led to the activation of multiple signaling pathways involved in cell proliferation and cancer stem cell development, to increased inflammation, and to the appearance of gastric intraepithelial neoplasia and tumorigenesis.…”

Section: Microbial Agents In Gastric Cancermentioning

confidence: 99%

Review: Gastric malignancies: Basic aspects

2019

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Gastric cancer is the third deadliest cancer in the world, and the absolute number of cases is increasing every year due to aging and growing of high‐risk populations. This disease is a consequence of the complex interaction of microbial agents, with environmental and host factors, resulting in the dysregulation of multiple oncogenic and tumor‐suppressing signaling pathways. Despite the advances in our understanding of carcinogenesis, there are still reduced therapeutic options for patients with gastric cancer. In recent years, genomic analyses of gastric tumors have emphasized their molecular heterogeneity. The distinction of gastric cancer molecular subtypes may be a key to identify novel therapeutic targets, to predict patient outcome and response to therapy, and to guide early diagnosis strategies. In this review, we summarize the most recent updates on the relationship between microbial agents and gastric cancer, in particular, Helicobacter pylori, the non‐H pylori microbiome, and Epstein‐Barr virus. We also highlight the main advances made in the past year regarding the molecular characterization of gastric cancer, especially the signatures with potential clinical utility.

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Loss of Tight Junction Protein Claudin 18 Promotes Progressive Neoplasia Development in Mouse Stomach

Cited by 78 publications

References 66 publications

Clinical Significance of CLDN18.2 Expression in Diffuse-Type Metastatic Gastric Cancer

Clinical Significance of CLDN18.2 Expression in Diffuse-Type Metastatic Gastric Cancer

Parietal cell-Specific SLC26A9 Deletion induces spontaneous Gastric Carcinogenesis in Mice

Review: Gastric malignancies: Basic aspects

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