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

  • Annika Jögi
  • Ingrid Øra
  • Helén Nilsson
  • Åsa Lindeheim
  • Yuichi Makino
  • Lorenz Poellinger
  • Håkan Axelson
  • Sven Påhlman
Publishing year: 2002
Language: English
Pages: 7021-7026
Publication/Series: Proceedings of the National Academy of Sciences
Volume: 99
Issue: 10
Document type: Journal article
Publisher: National Acad Sciences

Abstract english

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.


  • Pediatrics
  • Cancer and Oncology
  • Non-U.S. Gov't
  • Support
  • Phenotype
  • Chromaffin : cytology
  • Paraganglia
  • Oxygen : metabolism
  • Neuropeptide Y : genetics
  • Neuroblastoma
  • Neural Crest : cytology
  • Experimental
  • Neoplasms
  • Nude
  • Mice
  • Lymphokines : genetics
  • Insulin-Like Growth Factor II : genetics
  • Human
  • Helix-Loop-Helix Motifs
  • Hela Cells
  • Trans-Activators : genetics
  • Trans-Activators : metabolism
  • Transcription Factors : genetics
  • Transcription Factors : metabolism
  • Heterologous
  • Transplantation
  • Tumor Cells
  • Cultured
  • Tyrosine 3-Monooxygenase : genetics
  • Sympathetic Nervous System : metabolism
  • Gene Expression
  • Female
  • Endothelial Growth Factors : genetics
  • Down-Regulation
  • DNA-Binding Proteins : genetics
  • Cell Hypoxia
  • Biological Markers
  • Animal


  • Clinical Chemistry, Malmö
  • ISSN: 1091-6490
Sven Påhlman
E-mail: sven [dot] pahlman [at] med [dot] lu [dot] se


Division of Translational Cancer Research

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