HIF-2α promotes the formation of vasculogenic mimicry in pancreatic cancer by regulating the binding of Twist1 to the VE-cadherin promoter
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Jian Yang1,2*, Dong-Ming Zhu1,2*, Xiao-Gang Zhou1*, Ni Yin3, Yi Zhang1,2, Zi-Xiang Zhang1,2, De-Chun Li1,2 and Jian Zhou1,2
1Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
2Pancreatic Disease Research Center, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
3Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China
*Authors share co-first authorship
Jian Zhou, email: [email protected]
Keywords: vasculogenic mimicry (VM), HIF-2α, Twist, VE-cadherin, pancreatic cancer
Received: October 31, 2016 Accepted: February 02, 2017 Published: May 18, 2017
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-2α) promotes the progress of EMT in pancreatic cancer; however, whether HIF-2α promotes VM formation in pancreatic cancer remains unknown. In this study, we investigated HIF-2α expression and VM by immunohistochemistry in 70 pancreatic cancer patients as well as the role of Twist1and Twist2 in HIF-2α-induced VM in vitro and in vivo. We found that the overexpression of HIF-2α 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-2α in SW1990 cells induced VM formation, whereas the opposite results were found after silencing HIF-2α in AsPC-1 cells. A mechanistic study indicated that HIF-2α 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-2α increased Twist1 expression and promoted tumor growth and VM formation in pancreatic cancer xenografts in nude mice. These findings indicated that HIF-2α might play a critical role in VM and that HIF-2α and the pathway of HIF-2α inducing VM formation are potential therapeutic targets for pancreatic cancer.
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