6533b851fe1ef96bd12a99a8
RESEARCH PRODUCT
Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma: HIF-2α promotes an aggressive phenotype
Erik FredlundKatarina GradinLorenz PoellingerSven PåhlmanSamuel NavarroRosa NogueraAlexander PietrasHelén NilssonJohan Vallon-christerssonLinda Holmquist-mengelbierTobias LöfstedtÅKe Borgsubject
Transcriptional ActivationCancer ResearchProcollagen-Proline DioxygenaseAggressive phenotypeCELLCYCLEBiologyMiceNeuroblastomaNeuroblastomaBasic Helix-Loop-Helix Transcription FactorsTumor Cells CulturedmedicineAnimalsHumansRNA MessengerChildHypoxiaGeneOligonucleotide Array Sequence AnalysisRegulation of gene expressionGene knockdownGene Expression ProfilingCell BiologyCell cycleHypoxia (medical)Hypoxia-Inducible Factor 1 alpha Subunitmedicine.diseaseIn vitroGene Expression Regulation NeoplasticOxygenPhenotypeOncologyImmunologyCancer researchFemalemedicine.symptomNeoplasm Transplantationdescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2006-11-01 | Cancer Cell |