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

Annika Jögi; Ingrid Øra; Helén Nilsson; Asa Lindeheim; Yuichi Makino; Lorenz Poellinger; Håkan Axelson; Sven Påhlman

doi:10.1073/pnas.102660199

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

Proc Natl Acad Sci U S A. 2002 May 14;99(10):7021-6. doi: 10.1073/pnas.102660199.

Authors

Annika Jögi¹, Ingrid Øra, Helén Nilsson, Asa Lindeheim, Yuichi Makino, Lorenz Poellinger, Håkan Axelson, Sven Påhlman

Affiliation

¹ Department of Laboratory Medicine, Division of Molecular Medicine, Lund University, University Hospital MAS, S-205 02 Malmö, Sweden.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors
Biomarkers
Cell Hypoxia
DNA-Binding Proteins / genetics
Down-Regulation
Endothelial Growth Factors / genetics
Female
Gene Expression*
HeLa Cells
Helix-Loop-Helix Motifs
Humans
Hypoxia-Inducible Factor 1, alpha Subunit
Insulin-Like Growth Factor II / genetics
Lymphokines / genetics
Mice
Mice, Nude
Neoplasms, Experimental
Neural Crest / cytology*
Neuroblastoma
Neuropeptide Y / genetics
Oxygen / metabolism*
Paraganglia, Chromaffin / cytology
Phenotype
Sympathetic Nervous System / metabolism
Trans-Activators / genetics
Trans-Activators / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism
Transplantation, Heterologous
Tumor Cells, Cultured
Tyrosine 3-Monooxygenase / genetics
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors

Substances

ASCL1 protein, human
Ascl1 protein, mouse
Basic Helix-Loop-Helix Transcription Factors
Biomarkers
DNA-Binding Proteins
Endothelial Growth Factors
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Lymphokines
Neuropeptide Y
Trans-Activators
Transcription Factors
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors
endothelial PAS domain-containing protein 1
Insulin-Like Growth Factor II
Tyrosine 3-Monooxygenase
Oxygen