HIF-2α promotes the formation of vasculogenic mimicry in pancreatic cancer by regulating the binding of Twist1 to the VE-cadherin promoter

Vasculogenic mimicry (VM) is a blood supply modality that occurs independently of endothelial cell angiogenesis. Hypoxia and the epithelial-mesenchymal transition (EMT) induce VM formation by remodeling the extracellular matrix. Our previous study demonstrated that hypoxia-inducible factor-2 alpha (HIF-2 alpha) promotes the progress of EMT in pancreatic cancer; however, whether HIF-2 alpha promotes VM formation in pancreatic cancer remains unknown. In this study, we investigated HIF-2 alpha expression and VM by immunohistochemistry in 70 pancreatic cancer patients as well as the role of Twist1and Twist2 in HIF-2 alpha-induced VM in vitro and in vivo. We found that the overexpression of HIF-2 alpha and VM were correlated with poor tumor differentiation, late clinical stage and lymph node metastasis, and a poor prognosis in pancreatic cancer. Moreover, the upregulation of HIF-2 alpha in SW1990 cells induced VM formation, whereas the opposite results were found after silencing HIF-2 alpha in AsPC-1 cells. A mechanistic study indicated that HIF-2 alpha might regulate the binding of twist1 to vascular endothelial cadherin (VE-cadherin) to promote VM formation in pancreatic cancer cells, and that the P1 (-421bp) and P4 (-2110bp) regions of the Twist1 binding sequences are positive regulatory elements for VE-cadherin. In addition, we confirmed that the overexpression of HIF-2 alpha increased Twist1 expression and promoted tumor growth and VM formation in pancreatic cancer xenografts in nude mice. These findings indicated that HIF-2 alpha might play a critical role in VM and that HIF-2 alpha and the pathway of HIF-2 alpha inducing VM formation are potential therapeutic targets for pancreatic cancer.