Hypoxia-inducible factor-2a promotes tumor progression and has crosstalk with Wnt/β-catenin signaling in pancreatic cancer

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