H. pylori ‐induced NF‐κB‐PIEZO1‐YAP1‐CTGF axis drives gastric cancer progression and cancer‐associated fibroblast‐mediated tumour microenvironment remodelling

作者：Bonan Chen, Xiaoli Liu, Peiyao Yu, Fuda Xie, Johnny S. H. Kwan, Wai Nok Chan, Canbin Fang, Jinglin Zhang, Alvin H.K. Cheung, Chit Chow, Gloria W. M. Leung, Kam Tong Leung, Shihua Shi, Bin Zhang, Shouyu Wang, Dazhi Xu, Kaili Fu, Chi Chun Wong, William Ka Kei Wu, Michael W.Y. Chan, Patrick Ming‐Kuen Tang, Chi Man Tsang, Kwok Wai Lo, Gary M. Tse, Jun Yu, Ka‐Fai To, Wei Kang · 发表于：Clinical and Translational Medicine · 年份：2023 · DOI：10.1002/ctm2.1481 · 被引用次数：78 · 研究领域：Hippo pathway signaling and YAP/TAZ、Connective Tissue Growth Factor Research、Proteoglycans and glycosaminoglycans research

BACKGROUND: Gastric cancer (GC) is one of the most common tumours in East Asia countries and is associated with Helicobacter pylori infection. H. pylori utilizes virulence factors, CagA and VacA, to up-regulate pro-inflammatory cytokines and activate NF-κB signaling. Meanwhile, the PIEZO1 upregulation and cancer-associated fibroblast (CAF) enrichment were found in GC progression. However, the mechanisms of PIEZO1 upregulation and its involvement in GC progression have not been fully elucidated. METHODS: The CAF enrichment and clinical significance were investigated in animal models and primary samples. The expression of NF-κB and PIEZO1 in GC was confirmed by immunohistochemistry staining, and expression correlation was analysed in multiple GC datasets. GSEA and Western blot analysis revealed the YAP1-CTGF axis regulation by PIEZO1. The stimulatory effects of CTGF on CAFs were validated by the co-culture system and animal studies. Patient-derived organoid and peritoneal dissemination models were employed to confirm the role of the PIEZO1-YAP1-CTGF cascade in GC. RESULTS: Both CAF signature and PIEZO1 were positively correlated with H. pylori infection. PIEZO1, a mechanosensor, was confirmed as a direct downstream of NF-κB to promote the transformation from intestinal metaplasia to GC. Mechanistic studies revealed that PIEZO1 transduced the oncogenic signal from NF-κB into YAP1 signaling, a well-documented oncogenic pathway in GC progression. PIEZO1 expression was positively c...