Hypoxia-inducible Factor-2α Promotes EMT In Esophageal Squamous Cell Carcinoma Through The Notch Pathway

Background:Esophageal cancer is a common malignant digestive tumor with high incidence and mortality in the worldwide.The histopathological type of esophageal cancer is mainly divided into esophageal squamous cell carcinoma and esophageal adenocarcinoma.The pathogenesis of esophageal cancer has obvious regional characteristics.As a country with high incidence of esophageal cancer,the main pathological type in China is esophageal squamous cell carcinoma.At present,the clinical treatment of early esophageal squamous cell carcinoma still adopts comprehensive treatment measures mainly based on surgery and supplemented by radiotherapy and chemotherapy,but the treatment effect is unsatisfactory,and the five-year survival rate of patients is only 15%-20%.So it is vital important to clarify the mechanism of recurrence and metastasis and find specific therapy targets with high effect to improve prognosis of patients.Hypoxia-inducible factor2α(HIF-2α)is a member of hypoxia inducible factor family.It has been reported to function as oncogene in various kinds of tumors.But there is no study about HIF-2α and ESCC yet.Notch signaling pathway is an evolutionarily conserved signaling pathway that participates in a variety of cellular processes,including cell proliferation,differentiation,migration and embryo development.Previous studies have shown that overactivation of the Notch signaling pathway is observed in a variety of tumors,which always leads to various malignant biological behaviors of tumor cells,including proliferation,invasion,metastasis,and epithelial-mesenchymal transition.However,the specific mechanism of overactivation of Notch signaling pathway in esophageal squamous cell carcinoma is still unclear.ObjectiveIn this project,we aimed to investigate and illuminate the function of hypoxiainducible factor-2α(HIF-2α)in esophageal squamous cell carcinoma(ESCC).MethodsImmunohistochemistry and immunofluorescence were used to detect the expression of HIF-2α in tissues and cells.Clinicopathological data from 100 ESCC patients were used to investigate the relationship between HIF-2α and prognosis.Cell experiments(CCK8 assay and transwell migration assays)were utilized to verify the roles of HIF-2αon the ESCC cells.Western blotting was used to explore the mechanism of HIF-2α in ESCC.Mouse model was used to clarify the role of HIF-2α on ESCC cells in vivo.ResultsHIF-2α was overexpressed both in ESCC tissues and cells and corelated with poor prognosis in ESCC patients.CCK8 assay showed silencing HIF-2α suppressed proliferation of ESCC cells.Transwell assay showed overexpression of HIF-2α promoted the migration of ESCC cells.Western blot found HIF-2α regulated epithelialmesenchymal transition(EMT)through Notch pathway in ESCC cells.Mouse model showed silencing HIF-2α significantly suppressed the proliferation of ESCC cells in vivo.ConclusionIn conclusion,HIF-2α promotes epithelial-mesenchymal transition in esophageal squamous cell carcinoma through the Notch pathway.