A hypoxia-dependent upregulation of hypoxia-inducible factor-1 by nuclear factor-B promotes gastric tumour growth and angiogenesis

Abstract

Background:The underlying mechanisms involved in the activation of hypoxia-inducible factor-1 (HIF-1) in gastric cancer remain unclear. As nuclear factor-B (NF-B) as well as HIF-1 have been implicated in angiogenesis of various cancers, we investigated their relationship in gastric cancer.Methods:Nuclear expressions of HIF-1α and NF-B/RelA were assessed in 251 human gastric carcinoma specimens by immunohistochemical tissue array analysis. Stable human gastric cancer cells, infected with a retroviral vector containing super-suppressive mutant form of IBα (IBαM), were used for animal studies as well as cell culture experiments. Xenografted tumours were measured and IBαM effects on angiogenesis and HIF-1α activation were assessed by immunohistochemistry, western blotting, luciferase reporter assay, and semiquantitative reverse transcription-polymerase chain reaction. In addition, NF-B effects on the HIF-1α degradation and synthesis were examined.Results:Hypoxia-inducible factor-1α activation positively correlated with RelA activation in clinical gastric cancer samples (P0.001). The IBαM overexpression suppressed tumour growth, microvessel density, and HIF-1α activation in xenografted tumours. Cell culture experiments showed that hypoxia-induced HIF-1α expression was reduced by NF-B inhibition under hypoxic conditions at the translational level.Conclusion:The hypoxia-dependent activation of the NF-B/HIF-1α/VEGF pathway contributes, at least in part, to gastric cancer promotion via enhancement of angiogenesis. © 2011 Cancer Research UK All rights reserved.