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Oncotarget. 2017 Jul 18;8(29):47801-47815. doi: 10.18632/oncotarget.17999.

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

Yang J1,2, Zhu DM1,2, Zhou XG1, Yin N3, Zhang Y1,2, Zhang ZX1,2, Li DC1,2, Zhou J1,2.

Author information

1
Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.
2
Pancreatic Disease Research Center, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.
3
Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215006, China.

Abstract

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.

KEYWORDS:

HIF-2α; Twist; VE-cadherin; pancreatic cancer; vasculogenic mimicry (VM)

PMID:
28599281
PMCID:
PMC5564606
DOI:
10.18632/oncotarget.17999
[Indexed for MEDLINE]
Free PMC Article

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