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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) 1α and HIF-2α are key transcription regulators of phenotypic adaptation to low oxygen levels. Moreover, mouse gene disruption studies have implicated HIF-2α in embryonic regulation of t...

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Bibliographic Details
Published in:	Proceedings of the National Academy of Sciences - PNAS 2002-05, Vol.99 (10), p.7021-7026
Main Authors:	Jögi, Annika, Øra, Ingrid, Nilsson, Helén, Lindeheim, Åsa, Makino, Yuichi, Poellinger, Lorenz, Axelson, Håkan, Påhlman, Sven
Format:	Article
Language:	English
Subjects:	Animal Animals Basic Helix-Loop-Helix Transcription Factors Biological Markers Biological Sciences Biomarkers Cancer and Oncology Cancer och onkologi Cell Hypoxia Cell lines Cells Cellular differentiation Chromaffin : cytology Chromaffin cells Clinical Medicine Cultured DNA-Binding Proteins - genetics Down-Regulation Endothelial Growth Factors - genetics Experimental Female Gene Expression Genes HeLa Cells Helix-Loop-Helix Motifs Heterologous Human Humans Hypoxia Hypoxia-Inducible Factor 1, alpha Subunit hypoxia-inducible factor 1a hypoxia-inducible factor 2a Insulin-Like Growth Factor II - genetics Klinisk medicin Lymphokines - genetics Medical and Health Sciences Medicin och hälsovetenskap Mice Mice, Nude Neoplasms Neoplasms, Experimental Nervous system Neural Crest - cytology Neuroblastoma Neurons Neuropeptide Y - genetics Non-U.S. Gov't Nude Oxygen Oxygen - metabolism Paraganglia Paraganglia, Chromaffin - cytology Pediatrics Pediatrik Phenotype Phenotypes Rodents Studies Support Sympathetic Nervous System - metabolism Trans-Activators - genetics Trans-Activators - metabolism Transcription Factors - genetics Transcription Factors - metabolism Transplantation Transplantation, Heterologous Tumor cell line Tumor Cells Tumor Cells, Cultured Tumors Tyrosine 3-Monooxygenase - genetics Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factors
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Summary:	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 HIF-2α 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-1α and HIF-2α 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.
ISSN:	0027-8424 1091-6490 1091-6490
DOI:	10.1073/pnas.102660199