Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer

Peter Büchler, Howard A Reber, Manuela Büchler, Shailesh Shrinkante, Markus W Büchler, Helmut Friess, Gregg L Semenza, Oscar J Hines
Pancreas 2003, 26 (1): 56-64

INTRODUCTION: The microenvironment of low oxygen that is present in human pancreatic cancer in vivo may actively influence tumor growth as well as neovascularization.

AIMS: To determine whether hypoxia-inducible factor 1 (HIF-1) is specifically activated by hypoxia in vitro in pancreatic cancer cells and correlated these findings with tumor specimens.

METHODOLOGY: Hypoxic regulation of vascular endothelial growth factor (VEGF) was studied by northern blot analysis and enzyme-linked immunosorbent assay. Electrophoretic mobility shift assays and western blot analysis were used to demonstrate hypoxic activation of HIF-1. The relationship between HIF-1 and VEGF in human pancreatic cancer specimens was studied by immunohistochemical analysis, northern blot analysis, and in situ hybridization.

RESULTS: Studies in vivo of human pancreatic cancer tissue showed co-localization of VEGF mRNA, which is produced in ductal cancer cells, and HIF-1alpha protein, which was detectable in cell nuclei of the same cells. HIF-1alpha mRNA expression was dramatically upregulated (approximately 13-fold) in these specimens as well. In vitro, all pancreatic cancer cell lines increased VEGF production when exposed to low oxygen levels, by highly specific activation of HIF-1 DNA binding activity to the VEGF promoter. Cancer cell lines with high constitutive levels of HIF-1alpha protein were found to produce higher basal levels of VEGF.

CONCLUSION: We conclude that HIF-1 is the regulatory link between tumor hypoxia and VEGF production in pancreatic cancer, thus establishing a biochemical pathway between tumor hypoxia and neoangiogenesis in this highly aggressive neoplasm.

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