Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype.
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.
Holmquist-Mengelbier
Linda
L
Division of Molecular Medicine, Department of Laboratory Medicine, Lund University, University Hospital MAS, SE-205 02 Malmö, Sweden.
Fredlund
Erik
E
Löfstedt
Tobias
T
Noguera
Rosa
R
Navarro
Samuel
S
Nilsson
Helén
H
Pietras
Alexander
A
Vallon-Christersson
Johan
J
Borg
Ake
A
Gradin
Katarina
K
Poellinger
Lorenz
L
Påhlman
Sven
S
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002648:Child; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D011393:Procollagen-Proline Dioxygenase; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse