FGFR4 Gly388Arg Polymorphism Affects the Progression of Gastric Cancer by Activating STAT3 Pathway to Induce Epithelial to Mesenchymal Transition

PURPOSE:Fibroblast growth factor receptor 4 (FGFR4) plays a critical role in cancer progression involving in tumor proliferation, invasion, and metastasis. This study clarified the role of FGFR4-Arg388 variant in gastric cancer (GC), and more importantly highlighted the possibility of this single nucleotide polymorphism (SNP) as potential therapeutic targets.MATERIALS AND METHODS:FGFR4 polymorphism was characterized in advanced GC patients to perform statistical analysis. FGFR4-dependent signal pathways involving cell proliferation, invasion, migration, and resistance to oxaliplatin (OXA) in accordance with the SNP were also assessed in transfected GC cell lines.RESULTS:Among 102 GC patients, the FGFR4-Arg388 patients showed significantly higher tumor stage (p=0.047) and worse overall survival (p=0.033) than the Gly388 patients. Immunohistochemical results showed that FGFR4-Arg388 patients were more likely to have higher vimentin (p=0.025) and p-STAT3 (p=0.009) expression compared with FGFR4-Gly388 patients. In transfected GC cells, the overexpression of FGFR4-Arg388 variant increased proliferation and invasion of GC cells, increasing resistance of GC cells to OXA compared with cells overexpressing the Gly388 allele.CONCLUSION:The exploration mechanism may be through FGFR4-Arg388/STAT3/epithelial to mesenchymal transition axis regulating pivotal oncogenic properties of GC cells. The FGFR4-Arg388 variant may be a biomarker and a candidate target for adjuvant treatment of GC.