Recruitment of HIF-1α and HIF-2α to common target genes is differentially regulated in neuroblastoma:: HIF-2α promotes an aggressive phenotype

In neuroblastoma specimens, HIF-2 alpha but not HIF-1 alpha is strongly expressed in well-vascularized areas. In vitro, HIF-2 alpha protein was stabilized at 5% O-2 (resembling end capillary oxygen conditions) and, in contrast to the low HIF-1a activity at this oxygen level, actively transcribed genes like VEGF. Under hypoxia (1% O-2), HIF-1 alpha was transiently stabilized and primarily mediated acute responses, whereas HIF-2 alpha protein gradually accumulated and governed prolonged hypoxic gene activation. Knockdown of HIF-2 alpha reduced growth of neuroblastoma tumors in athymic mice. Furthermore, high HIF-2 alpha 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-2 alpha in neuroblastorna progression and have general tumor biological implications.