Abstract
Abstract Background: Helicobacter pylori (H. pylori) is the major cause of gastric cancer. Fibroblast growth factor receptor 4 (FGFR4) is a member of the highly conserved tyrosine kinase family known to be activated in cancer. Nuclear Factor Erythroid 2-Related Factor 2 (NRF2), a transcription factor, is essential for the antioxidant response and exhibits cytoprotective properties against cellular stress and oxidative damage. This study investigates the novel functions of FGFR4 and its role in regulating the antioxidant response in gastric tumorigenesis. Methods: We used public datasets, gastric tissues from mice and human, and gastric cancer cell lines. In vitro and in vivo H. pylori infections were performed. Western blot, RT-qPCR, Immunofluorescence, flow cytometry, Immunohistochemistry, Immunoprecipitation, Proximity ligation assay and Luciferase reporter assays were performed. Results: The analysis of a public dataset revealed that overexpression of FGFR4 is associated with an oxidative stress signature and poor survival. Gene set enrichment analysis (GSEA) showed that tissue samples with high FGFR4 levels had an enrichment of NRF2 signature genes. In vitro cell models infected with H. pylori showed an increase in reactive oxygen species (ROS). Knockdown of FGFR4 resulted in significant reductions in NRF2 protein and transcriptional activity, leading to increased ROS levels and DNA damage. Immunofluorescence analysis using various models confirmed that FGFR4 knockdown reversed the accumulation of NRF2 in the nucleus. Dysplastic and neoplastic gastric lesions in the TFF1-KO mouse model exhibited high levels of both FGFR4 and NRF2. Pharmacologic inhibition or knockdown of FGFR4 significantly decreased NRF2 levels, as well as the size and number of gastric cancer spheroids. Mechanistically, elevated levels of P62 protein were associated with FGFR4 expression. Binding between FGFR4 and P62 proteins, which competes with NRF2-KEAP1 interaction, was detected using immunoprecipitation and proximity ligation assay. Immunohistochemistry analysis on a tissue microarray showed increased FGFR4 immunostaining in HGD/Cancer samples compared to adjacent normal samples, and this increase correlated with an increase in NRF2 and P62 levels. Conclusion: These findings revealed that FGFR4 has a distinct functional role in promoting gastric carcinogenesis. FGFR4 binds to P62 to inhibit the interaction between NRF2 and KEAP1, allowing NRF2 to avoid degradation facilitating its translocation and accumulation in the nucleus. The use of FGFR4 inhibitors is a viable treatment option that warrants further research in patients with gastric cancer. Citation Format: Nadeem S. Bhat, Mohammed Soutto, Xing Zhang, Zheng Chen, Shoumin Zhu, Selma Maacha, Melanie Genoula, Dunfa Peng, Heng Lu, Oliver G McDonald, Xi Steven Chen, Longlong Cao, Zekuan Xu, Wael El-Rifai. FGFR4 mediates nuclear accumulation of NRF2 by binding to P62 in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 638.