2. Academic Validation
  3. H. pylori-induced NF-κB-PIEZO1-YAP1-CTGF axis drives gastric cancer progression and cancer-associated fibroblast-mediated tumour microenvironment remodelling

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

  • Clin Transl Med. 2023 Nov;13(11):e1481. doi: 10.1002/ctm2.1481.
Bonan Chen 1 2 3,  Xiaoli Liu 1 2 3,  Peiyao Yu 4,  Fuda Xie 1 2 3,  Johnny S H Kwan 1,  Wai Nok Chan 1,  Canbin Fang 1,  Jinglin Zhang 1,  Alvin H K Cheung 1,  Chit Chow 1,  Gloria W M Leung 5,  Kam Tong Leung 5,  Shihua Shi 6 7,  Bin Zhang 8,  Shouyu Wang 9,  Dazhi Xu 10,  Kaili Fu 2 11,  Chi Chun Wong 2 11,  William K K Wu 12,  Michael W Y Chan 13,  Patrick M K Tang 1,  Chi Man Tsang 1,  Kwok Wai Lo 1,  Gary M K Tse 1,  Jun Yu 2 11,  Ka Fai To 1 2,  Wei Kang 1 2 3
Affiliations

Affiliations

  • 1 Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
  • 2 Institute of Digestive Disease, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.
  • 3 CUHK-Shenzhen Research Institute, Shenzhen, China.
  • 4 Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
  • 5 Department of Pediatrics, The Chinese University of Hong Kong, Hong Kong, China.
  • 6 Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
  • 7 Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
  • 8 Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
  • 9 Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
  • 10 Department of Gastric Surgery, Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.
  • 11 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
  • 12 Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China.
  • 13 Department of Life Science, National Chung Cheng University, Chiayi, Taiwan.
PMID: 37983931 DOI: 10.1002/ctm2.1481
Abstract

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.

Keywords

CTGF; H. pylori; NF-κB; PIEZO1; YAP1; cancer-associated fibroblast; gastric cancer.

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