HIF-2α promotes epithelial-mesenchymal transition through regulating Twist2 binding to the promoter of E-cadherin in pancreatic cancer

Citations of this article
Mendeley users who have this article in their library.


BACKGROUND: Epithelial-mesenchymal transition (EMT) is a dedifferentiation process that mainly involves in mesenchymal marker upregulation, epithelial maker downregulation and cell polarity loss. Related hypoxia factors play a crucial role in EMT, however, it remains few evidence to clarify the role of HIF-2alpha in EMT in pancreatic cancer. METHOD: In this study, we investigated the expression of HIF-2alpha and E-cadherin by immunohistochemistry in 70 pancreatic cancer patients, as well as the correlation to the clinicopathologic characteristics. Then we regulated the expression of HIF-2alpha in pancreatic cancer cells to examine the role of HIF-2alpha on invasion and migration in vitro. Finally, we tested the relation of HIF-2alpha and EMT related proteins by Western blot and determined whether HIF-2alpha regulated EMT through Twist regulating the expression of E-cadherin by Chromatin immunoprecipitation (ChIP) assay. RESULTS: We found that HIF-2alpha protein was expressed positively in 67.1% (47/70) of pancreatic cancer tissues and 11.4% (8/70) of adjacent non-tumor pancreatic tissues, and there was a significant difference in the positive rate of HIF-2alpha protein between two groups (chi2 = 45.549, P < 0.05). In addition, the staining for HIF-2alpha was correlated with tumor differentiation (P < 0.05), clinical stage (P < 0.05) and lymph node metastasis (P < 0.05), while E-cadherin expression was only correlated with lymph node metastasis (P < 0.05). HIF-2alpha promoted cell migration, invasion in vitro, and regulated the expression of E-cadherin and MMPs, which are critical to EMT. Our further ChIP assay suggested that only Twist2 could bind to the promoter of E-cadherin in -714 bp region site, but there is no positive binding capacity in -295 bp promoter region site of E-cadherin. Clinical tissues IHC staining showed that Twist2 and E-cadherin expression had an obviously negative correlation in pancreatic cancer. Nevertheless, it had no obvious correlation between Twist1 and E-cadherin. CONCLUSION: These findings indicated that HIF-2alpha promotes EMT in pancreatic cancer by regulating Twist2 binding to the promoter of E-cadherin, which meant that HIF-2alpha and this pathway may be effective therapeutic targets for pancreatic cancer.




Yang, J., Zhang, X., Zhang, Y., Zhu, D., Zhang, L., Li, Y., … Zhou, J. (2016). HIF-2α promotes epithelial-mesenchymal transition through regulating Twist2 binding to the promoter of E-cadherin in pancreatic cancer. Journal of Experimental and Clinical Cancer Research, 35(1). https://doi.org/10.1186/s13046-016-0298-y

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free