HTRA1 promotes transdifferentiation of normal fibroblasts to cancer-associated fibroblasts through activation of the NF-κB/bFGF signaling pathway in gastric cancer

Abstract Cancer-associated fibroblasts comprise the major stromal cell populations in gastric cancer, which is a significant contributor to cancer-related death worldwide. As a member of the serine protease family, HTRA1 is reportedly involved in malignant transformation of various tumor types. In the present study, we observed that HTRA1 is positively correlated with α-SMA expression in gastric cancer tissues, which was also confirmed by correlation analysis and Gene Set Enrichment Analysis (GSEA) using the GEO database. Upregulation of HTRA1 in gastric cancer cell lines induces expression of α-SMA in normal fibroblasts. To explore how HTRA1 activates normal fibroblasts, an ELISA assay was performed. Secretion of bFGF/FGF2 from gastric cancer cells was significantly increased in response to HTRA1 overexpression. However, upreguation of α-SMA in normal fibroblasts induced by HTRA1 was restored by inhibiting the expression of bFGF. Furthermore, HTRA1 promotes bFGF/FGF2 expression through activation of NF-κB signaling in gastric cancer cells. Inhibition of the NF-κB signaling pathway partially restored baseline expression levels of α-SMA induced by HTRA1. In conclusion, HTRA1 promotes transdifferentiation of normal fibroblasts to cancer-associated fibroblasts by increasing bFGF/FGF2 expression, which is dependent upon activation of NF-κB signaling in gastric cancer.