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

Jögi, Annika LU ; Øra, Ingrid LU ; Nilsson, Helén LU ; Lindeheim, Åsa LU ; Makino, Yuichi; Poellinger, Lorenz; Axelson, Håkan LU and Påhlman, Sven LU (2002) In Proceedings of the National Academy of Sciences 99(10). p.7021-7026
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.... (More)
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. (Less)
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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
in
Proceedings of the National Academy of Sciences
volume
99
issue
10
pages
7021 - 7026
publisher
National Acad Sciences
external identifiers
  • wos:000175637300090
  • scopus:0037076385
ISSN
1091-6490
DOI
10.1073/pnas.102660199
language
English
LU publication?
yes
id
da912290-fea1-4ec4-8dd0-048b23fec1ae (old id 108252)
alternative location
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12011461&dopt=Abstract
date added to LUP
2007-07-25 14:30:34
date last changed
2017-10-22 03:42:49
@article{da912290-fea1-4ec4-8dd0-048b23fec1ae,
  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.},
  author       = {Jögi, Annika and Øra, Ingrid and Nilsson, Helén and Lindeheim, Åsa and Makino, Yuichi and Poellinger, Lorenz and Axelson, Håkan and Påhlman, Sven},
  issn         = {1091-6490},
  keyword      = {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},
  language     = {eng},
  number       = {10},
  pages        = {7021--7026},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype.},
  url          = {http://dx.doi.org/10.1073/pnas.102660199},
  volume       = {99},
  year         = {2002},
}