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

ABSTRACT

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.

KEYWORDS:

• H. pylori
• YAP
• β-catenin
• gastric carcinogenesis

Acknowledgments

We thank Prof. Richard Peek (Vanderbilt University Medical Center, Nashville, TN, USA) for kindly providing the H. pylori 7.13 strain. We also thank Xidong Wu (Department of Drug Safety Evaluation, Jiangxi Testing Center of Medical Instruments, Nanchang, China) for assistance with animal experiments.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

NSL, YZ and XBX conceived and designed the experiments; NSL, XBX, XF, YBOY, PZ and YAZ conducted in vivo and in vitro experiments; YZ contributed to the pathological analysis; CH, CX, YH, and JBH conducted the investigation; NSL, XBX and YZ contributed to data curation. NSL, ZMG, NHL, and YZ drafted and edited the manuscript; NSL and YZ supervised conducting of the study; NSL, NHL and YZ obtained funding of the study.

Data availability statements

The datasets supporting the conclusions of this article are included within the article and additional files.

Ethics approval and consent to participate

This study was approved by the ethics committee of The First Affiliated Hospital of Nanchang University (2020 (16)), and written informed consent was obtained from all patients.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2192501

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (81900500, 82260119, 82170580), the Natural Science Foundation of Jiangxi Province (20212BAB216016, 20224ACB216004), Doctoral Research Initiation Funding (701221002), and Young Medical Teacher Training Fund of Nanchang University (4209-16100009-PY201923).