Induction of Fibroblast Growth Factor Receptor 4 by Helicobacter pylori via Signal Transducer and Activator of Transcription 3 With a Feedforward Activation Loop Involving SRC Signaling in Gastric Cancer

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 163; no. 3; pp. 620 - 636.e9
• Main Authors: Zhang, Xing, Soutto, Mohammed, Chen, Zheng, Bhat, Nadeem, Zhu, Shoumin, Eissmann, Moritz F., Ernst, Matthias, Lu, Heng, Peng, Dunfa, Xu, Zekuan, El-Rifai, Wael
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2022
• Subjects: Animals; FGFR4; Gastric Cancer; Gastric Mucosa - pathology; H pylori; Helicobacter Infections - genetics; Helicobacter pylori - genetics; Humans; Inflammation - metabolism; Mice; Receptor, Fibroblast Growth Factor, Type 4 - genetics; Receptor, Fibroblast Growth Factor, Type 4 - metabolism; Receptors, Steroid - metabolism; RNA, Messenger - metabolism; SRC; STAT3; STAT3 Transcription Factor - metabolism; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; PBS; IL; KO; SRC; STAT3; qRT-PCR; GSEA; mRNA; siRNA; ChIP; H pylori; FGFR; TCGA; p; FBS; FGF19; Gastric Cancer; TFF1; FGFR4; WT
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2022.05.016

Helicobacter pylori (H pylori) infection is the main risk factor for gastric cancer. The role of fibroblast growth factor receptors (FGRFs) 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. 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, real-time quantitative reverse-transcription polymerase chain reaction, flow cytometry, immunofluorescence, immunohistochemistry, chromatin immunoprecipitation, and luciferase reporter assays were used for molecular, mechanistic, and functional studies. Analysis of FGFR family members using The Cancer Genome Atlas data, followed by validation, indicated that FGFR4 messenger (m)RNA 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 cytotoxin-associated gene A (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 signal transducer and activator of transcription 3 (STAT3). Analysis of the FGFR4 promoter suggested several putative binding sites for STAT3. Using chromatin immunoprecipitation assay and an FGFR-promoter luciferase reporter containing putative STAT3 binding sites and their mutants, we confirmed a direct functional binding of STAT3 on the FGFR4 promoter. Mechanistically, we also discovered a feedforward activation loop between FGFR4 and STAT3 where the fibroblast growth factor 19–FGFR4 axis played an essential role in activating STAT3 in a SRC proto-oncogene non-receptor tyrosine kinase dependent manner. Functionally, we found that FGFR4 protected against H pylori-induced DNA damage and cell death. Our findings demonstrated a link between infection, inflammation, and FGFR4 activation, where a feedforward activation loop between FGFR4 and STAT3 is established via SRC proto-oncogene non-receptor tyrosine kinase 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 patients with gastric cancer. [Display omitted] Helicobacter pylori infection is a key step driving a novel tumorigenic feedforward signaling loop linking infection, inflammation, and fibroblast growth factor receptor 4 activation in gastric cancer.