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

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.