Silencing of Hypoxia Inducible Factor-1α by RNA Interference Attenuates Human Glioma Cell Growth In vivo
Abstract
Purpose Higher-grade gliomas are distinguished by increased vascular endothelial cell proliferation and peritumoral edema. These are thought to be instigated by vascular endothelial growth factor, which, in turn, is regulated by cellular oxygen tension. Hypoxia inducible factor-1alpha (HIF-1alpha) is a main responder to intracellular hypoxia and is overexpressed in many human cancers, including gliomas. Experimental design We investigated the role of HIF-1alpha in glioma growth in vivo using RNA interference (RNAi) in U251, U87, and U373 glioma cells. Results We found that RNAi can be used to significantly attenuate glioma growth by reducing HIF-1alpha levels constitutively using short hairpin RNAs and transiently using small interfering RNAs (siRNA). HIF-1alpha levels on average were reduced 55% in normoxia and 71% in hypoxia. Vascular endothelial growth factor and GLUT-1 levels were reduced 81% and 71%, respectively, in the stable HIF-1alpha-reduced clones. These clones showed significant growth attenuation (up to 73%) compared with negative controls when grown in vivo in mouse flanks. Cellular proliferation was also reduced significantly, as determined by MIB-1 staining. Treating gliomas grown in mouse flank transiently with siRNA against HIF-1alpha by intratumoral injection resulted in a significant reduction of HIF-1alpha activity. This activity was followed using a hypoxia-responsive luciferase construct that enabled hypoxia imaging in vivo. Tumor volume in these siRNA…
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Genetic and pharmacological studies using inducible RNA interference against HIF-1α or HIF-2α demonstrated potent inhibition of tumor growth in animal models.
“Genetic and pharmacological studies using inducible RNA interference against HIF-1α or HIF-2α demonstrated potent inhibition of tumor growth in animal models [276,277].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [277]
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HIF inhibition: Current strategies and clinical challenges
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“Genetic and pharmacological studies using inducible RNA interference against HIF-1 α or HIF-2 α demonstrated potent inhibition of tumor growth in animal models [276,277].”
- Authors
- Gillespie, D. L., Whang, K., Ragel, B. T., Flynn, J. R., Kelly, D. A., & Jensen, R. L.
- Affiliations
- University of Utah (US)
- Venue
- Clinical Cancer Research
- Published
- 2007-04-15
- Volume
- 13
- Issue
- 8
- Pages
- 2441-2448
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2145281954
- Cited by
- 101
- References
- 3
- Citations by year
- 2026: 2 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 1 · 2016: 4 · 2015: 6 · 2014: 9 · 2013: 10 · 2012: 12
- FWCI
- 4.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- hypoxia-inducible factor-1α, glioma, RNA interference, siRNA, tumor growth inhibition, vascular endothelial growth factor, GLUT1, tumor hypoxia, hypoxia imaging, tumor angiogenesis, peritumoral edema, cell proliferation
- MeSH terms
- Animals, Cell Division, Glioma, Humans, Mice, Nude, Transfection, Transplantation, Heterologous, Polymerase Chain Reaction, Gene Silencing, RNA Interference, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit
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