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

Molecular Cancer

Research

Xu Sun¹  Qi Zhang²  Jingying Zhang²  Jiaqi Yang²  Xueli Bai²  Tingbo Liang²  Yu Lou²  Qihan Fu²  Tao Wei²  Qi Chen² 

[1] Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, 310009, Hangzhou, China;Department of General Surgery, Huzhou Central Hospital, Huzhou, China;Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road, 310009, Hangzhou, China;Key Laboratory of Pancreatic Diseases of Zhejiang Province, Hangzhou, China;

关键词: EPAS1;    PDAC;    Protein interaction;    Cancer stem cell;    Metabolic shift;   

DOI  :  10.1186/s12943-017-0689-5

 received in 2016-10-08, accepted in 2017-06-28,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundPancreatic 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.MethodsHerein, 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.ResultsFunctional assays revealed that hif-2α 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-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-2α was 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.ConclusionsOur systematic study revealed the roles of hif-2α in pancreatic cancer, and may provide a novel target for this highly malignant disease.

【 授权许可】

CC BY   
© The Author(s). 2017