4.7 Article

YAP and beta-catenin cooperate to drive H. pylori-induced gastric tumorigenesis

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GUT MICROBES
卷 15, 期 1, 页码 -

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TAYLOR & FRANCIS INC
DOI: 10.1080/19490976.2023.2192501

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H; pylori; YAP; beta-catenin; gastric carcinogenesis

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This study investigates the crosstalk between the Yes-associated protein 1 (YAP) and beta-catenin pathways in H. pylori-associated gastric tumorigenesis. The findings suggest that YAP and beta-catenin synergistically promote H. pylori-induced gastric carcinogenesis through their physical interaction, and identify CDX2, LGR5, and RUVBL1 as downstream genes shared by both pathways.
pylori infection is the strongest known risk factor for gastric carcinoma. The activation of the yesassociated protein 1 (YAP) and beta-catenin pathways has been associated with multiple tumor types. In this study, we investigated the crosstalk between the YAP and beta-catenin pathways in H. pyloriassociated gastric tumorigenesis. Immunohistochemical analysis of YAP and beta-catenin expression was performed in human gastric cancer tissues. The small molecules Super-TDU and KYA1797K, pharmacological inhibitors of YAP and beta-catenin, respectively, were used to investigate the role of these signaling pathways in H. pylori-induced gastric carcinogenesis in murine models of infection. The common downstream targets of YAP and beta-catenin signaling were evaluated by RNA sequencing (RNA-seq). Western blot, immunofluorescence, luciferase, RT-PCR, immunoprecipitation, cell counting kit-8 (CCK8), EdU and spheroid assays were used. H. pylori infection promoted YAP and beta catenin nuclear accumulation and transcriptional activity in gastric epithelial cells and transgenic insulin-gastrin (INS-GAS) mice, whereas silencing of both YAP and beta-catenin synergistically inhibited H. pylori-induced cell proliferation and expansion. In addition, YAP was found to directly interact with beta-catenin and knockdown of YAP suppressed H. pylori-induced nuclear translocation of beta-catenin. Moreover, downstream genes caudal-type homeobox 2 (CDX2), leucine-rich repeat containing G protein-coupled receptor 5 (LGR5) and RuvB like AAA ATPase 1 (RUVBL1) were shared by both YAP and beta-catenin signaling. Furthermore, treatment with the YAP inhibitor Super-TDU or beta-catenin inhibitor KYA1797A significantly alleviated gastric inflammation and epithelial DNA damage in H. pylori-infected mice. Finally, the elevation of gastric YAP was positively correlated with beta-catenin expression in human gastric cancer tissues. These findings indicate that YAP and beta catenin synergistically promote H. pylori-induced gastric carcinogenesis via their physical interaction and reveal that CDX2, LGR5 and RUVBL1 are the downstream genes shared by both the YAP and beta-catenin signaling pathways, and potentially contribute to H. pylori pathogenesis.

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