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

Research output: Contribution to journalArticle

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.

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Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Pediatrics
  • Cancer and Oncology

Keywords

  • 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
Original languageEnglish
Pages (from-to)7021-7026
JournalProceedings of the National Academy of Sciences
Volume99
Issue number10
Publication statusPublished - 2002
Publication categoryResearch
Peer-reviewedYes

Bibliographic note

The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Paediatrics (Lund) (013002000), Molecular Medicine (013031200), Division of Translational Cancer Research (013250500), Clinical Chemistry, Malmö (013016000)