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

• Published in: Clinical and translational medicine Vol. 13; no. 11; pp. e1481 - n/a
• Main Authors: Chen, Bonan, Liu, Xiaoli, Yu, Peiyao, Xie, Fuda, Kwan, Johnny S. H., Chan, Wai Nok, Fang, Canbin, Zhang, Jinglin, Cheung, Alvin H. K., Chow, Chit, Leung, Gloria W. M., Leung, Kam Tong, Shi, Shihua, Zhang, Bin, Wang, Shouyu, Xu, Dazhi, Fu, Kaili, Wong, Chi Chun, Wu, William K. K., Chan, Michael W. Y., Tang, Patrick M. K., Tsang, Chi Man, Lo, Kwok Wai, Tse, Gary M. K., Yu, Jun, To, Ka Fai, Kang, Wei
• Format: Journal Article
• Language: English
• Published: United States Wiley 01-11-2023
• Subjects: Animals; Cancer-Associated Fibroblasts - metabolism; cancer‐associated fibroblast; CTGF; gastric cancer; H. pylori; Helicobacter Infections - complications; Helicobacter Infections - genetics; Helicobacter Infections - metabolism; Helicobacter pylori - metabolism; Humans; Ion Channels; NF-kappa B - genetics; NF-kappa B - metabolism; NF‐κB; Peritoneal Neoplasms; PIEZO1; Stomach Neoplasms - pathology; Tumor Microenvironment - genetics; YAP1; YAP1; cancer-associated fibroblast; NF-κB; gastric cancer; PIEZO1; H. pylori; CTGF
• ISSN: 2001-1326; 2001-1326
• DOI: 10.1002/ctm2.1481

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 correlated with the YAP1 signature (CTGF, CYR61, and c‐Myc, etc.) in primary samples. The secreted CTGF by cancer cells stimulated the CAF infiltration to form a stiffened collagen‐enrichment microenvironment, thus activating PIEZO1 to form a positive feedback loop. Both PIEZO1 depletion by shRNA and CTGF inhibition by Procyanidin C1 enhanced the efficacy of 5‐FU in suppressing the GC cell peritoneal metastasis.
Conclusion
This study elucidates a novel driving PIEZO1‐YAP1‐CTGF force, which opens a novel therapeutic avenue to block the transformation from precancerous lesions to GC. H. pylori‐NF‐κB activates the PIEZO1‐YAP1‐CTGF axis to remodel the GC microenvironment by promoting CAF infiltration. Targeting PIEZO1‐YAP1‐CTGF plus chemotherapy might serve as a potential therapeutic option to block GC progression and peritoneal metastasis.
Description:
1. H. pylori induced NFκB directly regulates PIEZO1 transcription in gastric cancer (GC).
2. H. pylori prompts α‐SMA+ CAF accumulation in GC, driven by PIEZO1/YAP1/CTGF axis activation.
3. Enhanced microenvironment stiffness from augmented α‐SMA+ CAFs perpetuates PIEZO1 activation in a deleterious loop in GC.
4. Targeting CTGF with Procyanidin C1 emerges as a potential therapeutic strategy for H. pylori‐associated GC.