Abstract
In neuroblastoma specimens, HIF-2alpha but not HIF-1alpha is strongly expressed in well-vascularized areas. In vitro, HIF-2alpha protein was stabilized at 5% O2 (resembling end capillary oxygen conditions) and, in contrast to the low HIF-1alpha activity at this oxygen level, actively transcribed genes like VEGF. Under hypoxia (1% O2), HIF-1alpha was transiently stabilized and primarily mediated acute responses, whereas HIF-2alpha protein gradually accumulated and governed prolonged hypoxic gene activation. Knockdown of HIF-2alpha reduced growth of neuroblastoma tumors in athymic mice. Furthermore, high HIF-2alpha protein levels were correlated with advanced clinical stage and high VEGF expression and predicted poor prognosis in a clinical neuroblastoma material. Our results demonstrate the relevance of HIF-2alpha in neuroblastoma progression and have general tumor biological implications.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Child
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Female
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic*
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Humans
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Hypoxia
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Mice
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Neoplasm Transplantation
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Neuroblastoma / genetics
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Neuroblastoma / metabolism*
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Neuroblastoma / pathology
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Oligonucleotide Array Sequence Analysis
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Oxygen / metabolism
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Phenotype
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Procollagen-Proline Dioxygenase / genetics
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Procollagen-Proline Dioxygenase / metabolism
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RNA, Messenger / metabolism
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Transcriptional Activation
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Tumor Cells, Cultured
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Hif1a protein, mouse
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Hypoxia-Inducible Factor 1, alpha Subunit
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RNA, Messenger
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endothelial PAS domain-containing protein 1
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Procollagen-Proline Dioxygenase
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Oxygen