Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype

<jats:p> Insufficient oxygen and nutrient supply often restrain solid tumor growth, and the hypoxia-inducible factors (HIF) 1α and HIF-2α are key transcription regulators of phenotypic adaptation to low oxygen levels. Moreover, mouse gene disruption studies have implicated <jats:italic>HIF-2</jats:italic> α in embryonic regulation of <jats:italic>tyrosine hydroxylase</jats:italic> , 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-1α and HIF-2α proteins and activated the expression of known hypoxia-induced genes, such as <jats:italic>vascular endothelial growth factor</jats:italic> and <jats:italic>tyrosine hydroxylase</jats:italic> . 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 <jats:italic>c-kit</jats:italic> and <jats:italic>Notch-1</jats:italic> . Thus, hypoxia apparently causes dedifferentiation both <jats:italic>in vitro</jats:italic> and <jats:italic>in vivo</jats:italic> . These findings suggest a novel mechanism for selection of highly malignant tumor cells with stem-cell characteristics. </jats:p>