Hypoxia-inducible Factor-2α Promotes Tumor Progression And Has Crosstalk With Wnt/β-catenin Signaling In Pancreatic Cancer

Pancreatic cancer is a devastating disease that is characterized by persistent hypoxia.The roles of hypoxia-inducible factor-2α(hif-2α)are different to those of hif-1α,although both are critical for tumor cells to adapt to the hypoxic microenvironment.However,unlike the well-studied hif-1α,the role of hif-2α in tumors,including pancreatic cancer,is poorly understood.Herein,we used a mutated hif-2α(A530T)to figure out the problem that wild-type hif-2α is quickly degraded which limits the study of its function.Using several cell lines,mouse models,and human tissues,we obtained a general picture of hif-2α in pancreatic cancer progression.Functional assays revealed that hif-2α promotes epithelial-to-mesenchymal(EMT)transition,enhances tumor proliferation and invasion,increases sternness,and facilitates angiogenesis.We identified an interaction between hif-2α and β-catenin,and found that hif-2α/β-catenin complex formation increased the activity of β-catenin and the protein stability of hif-2α.In vivo study confirmed the pro-oncogenic role of hif-2α,whose expression correlated with those of E-cadherin,vimentin,Ki-67,and CD31,but not hif-1α.A human tissue study showed that hif-2αwas associated with lymph node metastasis,pathological grade,stroma abundance,vascularization and patient survival.High expression of hif-2α was also identified as an independent indicator of poor prognosis in patients with pancreatic cancer.Our systematic study revealed the roles of hif-2α in pancreatic cancer,and may provide a novel target for this highly malignant disease.