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

Research output: Contribution to journalArticle

Abstract

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-1α protein, which was detectable in cell nuclei of the same cells. HIF-1α mRNA expression was dramatically upregulated (≈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-1α 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.

Original languageEnglish (US)
Pages (from-to)56-64
Number of pages9
JournalPancreas
Volume26
Issue number1
DOIs
StatePublished - Jan 2003

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Hypoxia-Inducible Factor 1
Pancreatic Neoplasms
Vascular Endothelial Growth Factor A
Neoplasms
Northern Blotting
Oxygen
Cell Hypoxia
Cell Line
Messenger RNA
Electrophoretic Mobility Shift Assay
Cell Nucleus
In Situ Hybridization
Proteins
Western Blotting
Enzyme-Linked Immunosorbent Assay
DNA

ASJC Scopus subject areas

  • Gastroenterology
  • Endocrinology

Cite this

Büchler, P., Reber, H. A., Büchler, M., Shrinkante, S., Büchler, M. W., Friess, H., ... Hines, O. J. (2003). Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer. Pancreas, 26(1), 56-64. https://doi.org/10.1097/00006676-200301000-00010

Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer. / Büchler, Peter; Reber, Howard A.; Büchler, Manuela; Shrinkante, Shailesh; Büchler, Markus W.; Friess, Helmut; Semenza, Gregg L; Hines, Oscar J.

In: Pancreas, Vol. 26, No. 1, 01.2003, p. 56-64.

Research output: Contribution to journalArticle

Büchler, P, Reber, HA, Büchler, M, Shrinkante, S, Büchler, MW, Friess, H, Semenza, GL & Hines, OJ 2003, 'Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer', Pancreas, vol. 26, no. 1, pp. 56-64. https://doi.org/10.1097/00006676-200301000-00010
Büchler, Peter ; Reber, Howard A. ; Büchler, Manuela ; Shrinkante, Shailesh ; Büchler, Markus W. ; Friess, Helmut ; Semenza, Gregg L ; Hines, Oscar J. / Hypoxia-inducible factor 1 regulates vascular endothelial growth factor expression in human pancreatic cancer. In: Pancreas. 2003 ; Vol. 26, No. 1. pp. 56-64.
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