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

BACKGROUND: The underlying mechanisms involved in the activation of hypoxia-inducible factor-1 (HIF-1) in gastric cancer remain unclear. As nuclear factor-kappa B (NF-kappa 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-1 alpha and NF-kappa 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 IkB alpha (IkB alpha M), were used for animal studies as well as cell culture experiments. Xenografted tumours were measured and I kappa B alpha M effects on angiogenesis and HIF-1 alpha activation were assessed by immunohistochemistry, western blotting, luciferase reporter assay, and semiquantitative reverse transcription-polymerase chain reaction. In addition, NF-kappa B effects on the HIF-1 alpha degradation and synthesis were examined. RESULTS: Hypoxia-inducible factor-1 alpha activation positively correlated with RelA activation in clinical gastric cancer samples (P < 0.001). The I kappa B alpha M overexpression suppressed tumour growth, microvessel density, and HIF-1 alpha activation in xenografted tumours. Cell culture experiments showed that hypoxia-induced HIF-1 alpha expression was reduced by NF-kappa B inhibition under hypoxic conditions at the translational level. CONCLUSION: The hypoxia-dependent activation of the NF-kappa B/HIF-1 alpha/VEGF pathway contributes, at least in part, to gastric cancer promotion via enhancement of angiogenesis. British Journal of Cancer (2011) 104, 166-174. doi:10.1038/sj.bjc.6606020 www.bjcancer.com Published online 30 November 2010 (C) 2011 Cancer Research UK