Tumour cell-derived serglycin promotes IL-8 secretion of CAFs in gastric cancer

  • Br J Cancer. 2024 Jun 11. doi: 10.1038/s41416-024-02735-2.
Xiang Li  #  1 ,  Guiping Xie  #  1 ,  Jia Chen  #  2  3  4 ,  Yaohui Wang  5 ,  Jing Zhai  1 ,  Lizong Shen  6  7  8
Affiliations
  • 1. Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
  • 2. Department of General Surgery, the First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China.
  • 3. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China.
  • 4. Department of General Surgery, Northern Jiangsu People's Hospital, Yangzhou, 225001, China.
  • 5. Department of Pathology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
  • 6. Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China. [email protected].
  • 7. Department of General Surgery, the First Affiliated Hospital, Nanjing Medical University, Nanjing, 210029, China. [email protected].
  • 8. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China. [email protected].
  • # Contributed equally.
PMID: 38862740 DOI: 10.1038/s41416-024-02735-2
Abstract

Background: Cancer-associated fibroblasts (CAFs)-derived IL-8 plays important roles in chemoresistance, immunosuppression, and lymph node metastasis of gastric Cancer. However, the mechanisms underlying IL-8 production in CAFs remains unclear.

Methods: DNA pulldown assay was performed to identify the transcription factors responsible for IL-8 expression in CAFs, which was further verified using CHIP-qPCR and DNA Agarose gel electrophoresis assays. The cellular localisation of IL-8 was analysed using multiplex immunofluorescence (MxIF).

Results: MxIF demonstrated that IL-8 was mainly produced by CAFs in gastric Cancer. Lysine[K]-specific demethylase 5B (KDM5B) was identified as an IL-8 transcription factor in CAFs, and the binding of KDM5B to phosphorylated RB1 limited the transcriptional regulation of IL-8 in gastric Cancer cells. Serglycin (SRGN) secreted by tumour cells activated the CD44/c-Myc pathway to upregulate KDM5B expression, thereby promoting IL-8 production in CAFs. Furthermore, tumour-associated neutrophils (TANs)-derived regenerating family member 4 (REG4) upregulates SRGN expression by activating cAMP-responsive element binding protein 1 (CREB1) in gastric Cancer cells. Thus, the SRGN-IL-8-TANs-SRGN loop, which facilitates tumour progression, has been explored in gastric Cancer.

Conclusions: This study revealed the mechanisms of the preferential production of IL-8 by CAFs in gastric Cancer, and paves the way for potential new therapeutic strategies for gastric Cancer.

Products
Inhibitors & Agonists
Other Products