LAUSR

BACKGROUND & AIMS Helicobacter pylori (H. pylori) infection is the main risk factor for gastric cancer. The role of Fibroblast Growth Factor Receptors in H. pylori-mediated gastric tumorigenesis remains largely unknown. This study investigated the molecular and mechanistic links between H. pylori, inflammation, and FGFR4 in gastric cancer. METHODS Cell lines, human and mouse gastric tissue samples, and gastric organoids models were implemented. Infection with H. pylori was performed using in vitro and in vivo models. Western blot, quantitative real-time RT-PCR (qPCR), flow cytometry, immunofluorescence, immunohistochemistry, ChIP, and luciferase reporter assays were utilized for molecular, mechanistic and functional studies. RESULTS Analysis of FGFR family members using TCGA data, followed by validation, indicated that FGFR4 mRNA was the most significantly overexpressed member in human gastric cancer tissue samples (P < .001). We also detected high levels of Fgfr4 mRNA and protein in gastric dysplasia and adenocarcinoma lesions in mouse models. Infection with J166, 7.13, and PMSS1 CagA+ H. pylori strains induced FGFR4 mRNA and protein expression in in vitro and in vivo models. This was associated with a concordant activation of STAT3. Analysis of FGFR4 promoter suggested several putative binding sites for STAT3. Using ChIP assay and an FGFR-promoter luciferase reporter containing putative STAT3 binding sites and their mutants, we confirmed a direct functional binding of STAT3 on FGFR4 promoter. Mechanistically, we also discovered a feedforward activation loop between FGFR4 and STAT3 where the FGF19-FGFR4 axis played an essential role in activating STAT3 in a SRC-dependent manner. Functionally, we found that FGFR4 protected against H. pylori-induced DNA damage and cell death. CONCLUSION Our findings demonstrated a link between infection, inflammation and FGFR4 activation where a feedforward activation loop between FGFR4 and STAT3 is established via SRC in response to H. pylori infection. Given the relevance of FGFR4 to the etiology and biology of gastric cancer, we propose FGFR4 as a druggable molecular vulnerability that can be tested in gastric cancer patients.