Tumour cell-derived serglycin promotes IL-8 secretion of CAFs in gastric cancer
Menée à l'aide d'échantillons sanguins et d'échantillons tissulaires issus de patients atteints d'un cancer gastrique, cette étude met en évidence un mécanisme par lequel la serglycine sécrétée par les cellules tumorales favorise la production d'interleukine IL-8 par les fibroblastes CAFs
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.
British Journal of Cancer , article en libre accès, 2024