Inhibition of hypoxia inducible factor-1α (HIF-1α) decreases vascular endothelial growth factor (VEGF) secretion and tumor growth in malignant gliomas
- Randy L. JensenAffiliated withDepartment of Neurosurgery, University of UtahHuntsman Cancer Institute,, University of UtahDepartment of Neurosurgery, University of Utah Email author
- , Brian T. RagelAffiliated withDepartment of Neurosurgery, University of Utah
- , Kum WhangAffiliated withHuntsman Cancer Institute,, University of UtahYonsei University, Wonju College of Medicine
- , David GillespieAffiliated withDepartment of Neurosurgery, University of UtahHuntsman Cancer Institute,, University of Utah
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Hypoxia inducible factor-1α (HIF-1α) regulates vascular endothelial growth factor (VEGF), the presumed principal mediator of angiogenesis in malignant gliomas, under normal physiologic conditions. We examined the effect of HIF-1α on VEGF secretion, tumor growth, and angiogenesis in malignant gliomas.
We examined 175 human gliomas for expression of HIF-1α and its downstream-regulated proteins. HIF-1α expression and VEGF secretion in glioma cell lines under normoxia and hypoxia were examined using␣ELISA and Western blot. Malignant glioma cell lines were transfected with dominant-negative HIF-1α (DN-HIF-1α) expression vector or siRNA constructs against the HIF-1α gene. Growth studies were conducted on cells with the highest VEGF/HIF-1α inhibition isolated from stable transfected cell lines. MIB-1-labeling index and microvascular density (MVD) measurements were performed on the in vivo tumors.
HIF-1 expression correlates with malignant glioma phenotype and was not confined to perinecrotic, pseudopalisading cells. VEGF and HIF-1 expression was high in glioma cell lines even under normoxia, and increased after exposure to hypoxia or growth factor stimulation. Cells transfected with DN-HIF-1α or HIF-1α siRNA demonstrated decreased HIF-1α and VEGF secretion. In vivo but not in vitro growth decreased in response to VEGF and HIF-1 inhibition. HIF-1 siRNA studies showed decreased VEGF secretion and in vitro and in vivo growth of glioma cell lines. MVD was unchanged but MIB-1 proliferation index decreased for both types of HIF-1 inhibition.
VEGF and HIF-1α are elevated in malignant gliomas. HIF-1α inhibition results in VEGF secretion inhibition. HIF-1α expression affects glioma tumor growth, suggesting clinical applications for malignant glioma treatment.
Keywordsangiogenesis brain tumor glioblastoma multiforme hypoxia inducible factor siRNA vascular endothelial growth factor
- Inhibition of hypoxia inducible factor-1α (HIF-1α) decreases vascular endothelial growth factor (VEGF) secretion and tumor growth in malignant gliomas
Journal of Neuro-Oncology
Volume 78, Issue 3 , pp 233-247
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- Springer US
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- brain tumor
- glioblastoma multiforme
- hypoxia inducible factor
- vascular endothelial growth factor
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- Author Affiliations
- 1. Department of Neurosurgery, University of Utah, Salt Lake City, Utah, USA
- 2. Huntsman Cancer Institute,, University of Utah, Salt Lake City, Utah, USA
- 4. Department of Neurosurgery, University of Utah, 3B-409 SOM, 30 North 1900 East, Salt Lake City, Utah, 84132-2303, USA
- 3. Yonsei University, Wonju College of Medicine, Wonju, Korea