Nuclear Factor-&kgr;B-Dependent Epithelial to Mesenchymal Transition Induced by HIF-1&agr; Activation in Pancreatic Cancer Cells under Hypoxic Conditions.

Background: Epithelial to mesenchymal transition (EMT) induced by hypoxia is one of the critical causes of treatment failure in different types of human cancers. NF-&kgr;B is closely involved in the progression of EMT. Compared with HIF-1&agr;, the correlation between NF-&kgr;B and EMT during hypoxia has been less studied, and although the phenomenon was observed in the past, the molecular mechanisms involved remained unclear. Methodology/Principal Findings: Here, we report that hypoxia or overexpression of hypoxia-inducible factor-1&agr; (HIF-1&agr;) promotes EMT in pancreatic cancer cells. On molecular or pharmacologic inhibition of NF-&kgr;B, hypoxic cells regained expression of E-cadherin, lost expression of N-cadherin, and attenuated their highly invasive and drug-resistant phenotype. Introducing a pcDNA3.0/HIF-1&agr; into pancreatic cancer cells under normoxic conditions heightened NF-&kgr;B activity, phenocopying EMT effects produced by hypoxia. Conversely, inhibiting the heightened NF-&kgr;B activity in this setting attenuated the EMT phenotype. Conclusions/Significance: These results suggest that hypoxia or overexpression of HIF-1&agr; induces the EMT that is largely dependent on NF-&kgr;B in pancreatic cancer cells. [ABSTRACT FROM AUTHOR]