The Effect Of Blocking FGFR4 On Biological Behavior Of Esophageal Squamous Cell Carcinoma And Its Mechanism Studies

Background:Esophageal cancer is one of the most common cancers in the world.In China,the mortality of esophageal cancer ranks fourth among all cancers.Squamous cell carcinoma is the most common pathological type of esophageal cancer.Although early screening and treatment have improved,the overall therapeutic effect and clinical prognosis of esophageal cancer are still not satisfactory.The FGFR family can be activated by FGFs and plays important roles in regulating cell growth,differentiation,migration,and angiogenesis.FGFR4 is one of the family of fibroblast growth factor receptor.And recent studies have suggested that FGFR4 could regulate several processes,including tumor progression.However,the molecule mechanism and the potential roles of FGFR4 in ESCC remain unknown.The purpose of this study was to investigate the correlation between the expression of FGFR4 and the clinical prognosis of patients.And we further explored the effect of blocking of FGFR4 on malignant biological behavior of esophageal squamous cell carcinoma cells and its specific mechanism on cytological level.Objective:To explore the expression of FGFR4 in human esophageal squamous cell carcinoma(ESCC)specimens and cell lines,and to analyze the relationship between the expression of FGFR4 and prognosis of the patients.To observe the biological changes of esophageal squamous cell carcinoma after blocking FGFR4 and to explore the specific mechanisms of FGFR4 affecting the biological behaviors of ESCC.Methods:Immunohistochemistry and Western blotting were used to detect FGFR4 expression in ESCC samples and cell lines.The clinical data of 40 patients with esophageal squamous cell carcinoma was analyzed by statistical software,and the correlation between the expression of FGFR4 and prognosis of ESCC patients was studied.Cell counting kit-8,and clonogenic,transwell,flow cytometric,and tumor xenograft in nude mice assays were utilized to determine the effect of blocking FGFR4 in proliferation,invasion,migration,and apoptosis of ESCC cells.The activation of ERK and AKT pathway in ESCC cell lines after blocking FGFR4 was further detected by Western blotting assay.Results:FGFR4 is frequently overexpressed in ESCC tissue and cell lines.And the expression of FGFR4 was correlated with clinicopathological parameters and prognosis in ESCC patients.Vitro assays have shown that blocking FGFR4 by a specific blocker.H3B-6527,significantly decreases proliferation,invasion,and migration,and alters epithelial-mesenchymal transition markers in ESCC cells.In addition.FGFR4 blockade is associated with the induction of apoptosis and affects P13K/AKT and MAPK/ERK pathways.Moreover,FGFR4 blockade could significantly inhibit the growth of xenograft tumors in vivo.Conclusion:The positive expression of FGFR4 may promote the carcinogenesis and development of esophageal squamous cell carcinoma.Besides blocking FGFR4 significantly suppresses the malignant behaviors of ESCC by affecting AKT and ERK signaling pathways,which indicate that FGFR4 is a potential target for the treatment of ESCC.