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

by Selleckchem | Oct 26 2023

H. pylori infection is the strongest known risk factor for gastric carcinoma. The activation of the yes-associated protein 1 (YAP) and β-catenin pathways has been associated with multiple tumor types. In this study, we investigated the crosstalk between the YAP and β-catenin pathways in H. pylori-associated gastric tumorigenesis. Immunohistochemical analysis of YAP and β-catenin expression was performed in human gastric cancer tissues. The small molecules Super-TDU and KYA1797K, pharmacological inhibitors of YAP and β-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 β-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 β-catenin nuclear accumulation and transcriptional activity in gastric epithelial cells and transgenic insulin-gastrin (INS-GAS) mice, whereas silencing of both YAP and β-catenin synergistically inhibited H. pylori-induced cell proliferation and expansion. In addition, YAP was found to directly interact with β-catenin and knockdown of YAP suppressed H. pylori-induced nuclear translocation of β-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 β-catenin signaling. Furthermore, treatment with the YAP inhibitor Super-TDU or β-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 β-catenin expression in human gastric cancer tissues. These findings indicate that YAP and β-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 β-catenin signaling pathways, and potentially contribute to H. pylori pathogenesis.

Comments:

The study you described investigated the crosstalk between the Yes-associated protein 1 (YAP) and β-catenin pathways in the development of gastric cancer associated with Helicobacter pylori (H. pylori) infection. The researchers performed immunohistochemical analysis of YAP and β-catenin expression in human gastric cancer tissues. They also used small molecules called Super-TDU and KYA1797K, which are pharmacological inhibitors of YAP and β-catenin, respectively, to understand the role of these signaling pathways in H. pylori-induced gastric carcinogenesis using mouse models of infection.

The results of the study showed that H. pylori infection promoted the nuclear accumulation and transcriptional activity of both YAP and β-catenin in gastric epithelial cells and transgenic insulin-gastrin (INS-GAS) mice. When YAP and β-catenin were simultaneously silenced, it synergistically inhibited H. pylori-induced cell proliferation and expansion, suggesting that both proteins play a role in promoting tumor growth. The researchers also found that YAP directly interacted with β-catenin and that silencing YAP inhibited the nuclear translocation of β-catenin induced by H. pylori.

Furthermore, the study identified several downstream genes, including caudal-type homeobox 2 (CDX2), leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), and RuvB-like AAA ATPase 1 (RUVBL1), that were shared by both the YAP and β-catenin signaling pathways. These genes are potentially involved in H. pylori pathogenesis and contribute to gastric carcinogenesis.

Additionally, the researchers used inhibitors of YAP (Super-TDU) and β-catenin (KYA1797A) to treat H. pylori-infected mice and found that these inhibitors significantly alleviated gastric inflammation and epithelial DNA damage.

Finally, the study observed a positive correlation between the expression of YAP and β-catenin in human gastric cancer tissues, suggesting their cooperative role in gastric carcinogenesis.

In summary, this study demonstrates that YAP and β-catenin interact and synergistically promote H. pylori-induced gastric carcinogenesis. It also identifies CDX2, LGR5, and RUVBL1 as downstream genes shared by both pathways, potentially contributing to H. pylori pathogenesis. The findings highlight the significance of the YAP and β-catenin pathways in gastric cancer development and suggest potential therapeutic targets for H. pylori-associated gastric carcinoma.