Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype.
Insufficient oxygen and nutrient supply often restrain solid tumor growth, and the hypoxia-inducible factors (HIF) 1 alpha and HIF-2 alpha are key transcription regulators of phenotypic adaptation to low oxygen levels. Moreover, mouse gene disruption studies have implicated HIF-2 alpha in embryonic regulation of tyrosine hydroxylase, a hallmark gene of the sympathetic nervous system. Neuroblastoma tumors originate from immature sympathetic cells, and therefore we investigated the effect of hypoxia on the differentiation status of human neuroblastoma cells. Hypoxia stabilized HIF-1 alpha and HIF-2 alpha proteins and activated the expression of known hypoxia-induced genes, such as vascular endothelial growth factor and tyrosine hydroxylase. These changes in gene expression also occurred in hypoxic regions of experimental neuroblastoma xenografts grown in mice. In contrast, hypoxia decreased the expression of several neuronal/neuroendocrine marker genes but induced genes expressed in neural crest sympathetic progenitors, for instance c-kit and Notch-1. Thus, hypoxia apparently causes dedifferentiation both in vitro and in vivo. These findings suggest a novel mechanism for selection of highly malignant tumor cells with stem-cell characteristics.
Jögi
Annika
A
Department of Laboratory Medicine, Division of Molecular Medicine, Lund University, University Hospital MAS, S-205 02 Malmö, Sweden.
Øra
Ingrid
I
Nilsson
Helén
H
Lindeheim
Asa
A
Makino
Yuichi
Y
Poellinger
Lorenz
L
Axelson
Håkan
H
Påhlman
Sven
S
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D015687:Cell Hypoxia; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation; D016228:Endothelial Growth Factors / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006367:HeLa Cells; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008222:Lymphokines / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D009432:Neural Crest / Q000166:cytology*; D009447:Neuroblastoma; D009478:Neuropeptide Y / Q000235:genetics; D010100:Oxygen / Q000378:metabolism*; D010233:Paraganglia, Chromaffin / Q000166:cytology; D010641:Phenotype; D013564:Sympathetic Nervous System / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007335:Insulin-Like Growth Factor II; D008222:Lymphokines; D009478:Neuropeptide Y; D010100:Oxygen; D015534:Trans-Activators; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C065500:ASCL1 protein, human; C499317:Ascl1 protein, mouse; C497442:HIF1A protein, human