The Role Of Fibroblast Growth Factor Receptor 4 Gly388Arg Polymorphism In Gastric Cancer And Its Effect On Chemotherapy

Background and Objective: At present,the research on targeted therapy of gastric cancer has become a hot topic.Trastuzumab and Herceptin are treated with advanced gastric cancer,but the overall effect was not satisfactory.Therefore,whether new molecular targets play an important role in the occurrence and development of gastric cancer,whether there are further targeted drugs worthy of research and development will become a further breakthrough in the field of gastric cancer research.In recent years,there have been more and more researches on FGFR(Fibroblast growth factor receptor)family molecules.Some scholars believe that the FGFR family is an emerging field in the diagnosis and treatment of malignant tumors,and has broad application prospects.Fibroblast growth factor receptor 4(FGFR4)plays a critical role in cancer progression involving in tumor proliferation,invasion,and metastasis.This study elucidated the role of FGFR4-Arg388 variant in gastric cancer,and more importantly highlighted the possibility of this single nucleotide polymorphism(SNP)as potential therapeutic targets.The First Part: FGFR4-Arg388 Variant Promotes Gastric Cancer Progression And Increases Resistance to Oxaliplatin by Activating STAT3 Pathway to Induce Epithelial-to-Mesenchymal TransitionObjective: This study elucidated 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.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 genotypes 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(OS)(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 over-expression of FGFR4-Arg388 variant increased proliferation,invasion and infiltration of GC cells,increasing resistance of GC cells to OXA compared with cells over-expressing the Gly388 allele.The exploration mechanism may be through FGFR4-Arg388/STAT3(signal transducer and activator of transcription 3)/epithelial to mesenchymal transition(EMT)axis regulating pivotal oncogenic properties of GC cells.Conclusion: The FGFR4-Arg388 variant may be a biomarker and a candidate target for adjuvant treatment of GC.The Second Part: Silencing of FGFR4 Affects the Progression of Gastric Cancer by Mediating Epithelial-to-Mesenchymal Transition and STAT3 Pathways Objective: To investigate whether FGFR4 affects the function of gastric cancer cells and explore the association of FGFR4 with EMT and STAT3 signaling pathway.Methods: Sh RNA was used to silence FGFR4 expression in gastric cancer cells.FGFR4-dependent signal pathways involving cell proliferation,invasion and migration were also assessed in FGFR4-sh RNA gastric cancer cell lines.Results: Compared with mock and NC cells,the proliferation,invasion and migration of FGFR4-sh RNA cells was considerably decreased.Westtern bolt showed that the expression of STAT3,p-STAT3 and Vimentin were significantly decreased in the FGFR4-sh RNA group,while E-cadherin was elevated.Conclusion: Silencing FGFR4 expression affects the progression of gastric cancer,which may be due to the correlation between FGFR4 and EMT pathway and STAT3 pathway of gastric cancer.FGFR4 may become a potential biological target for the treatment of gastric cancer.Full text conclusion: Conclusion: Silencing FGFR4 expression or constructing FGFR4 over-expression cell lines could affect the biological characteristics of gastric cancer.Both models demonstrated the carcinogenicity of FGFR4 itself.It was worth emphasizing that FGFR4 Arg388 variation was more carcinogenic than Gly388 allele,which it can accelerate the progress of gastric cancer,weaken the chemotherapy effect of oxaliplatin,and be related to the poor prognosis of gastric cancer patients.FGFR4 and its Gly388 Arg polymorphism are worthy of further investigation in the targeted therapy of gastric cancer.