Human neuroblastoma cells exposed to hypoxia: induction of genes associated with growth, survival, and aggressive behavior.
We have recently found that cells derived from human neuroblastoma, a sympathetic nervous system (SNS) tumor, dedifferentiate and acquire a neural crest-like phenotype when exposed to hypoxia. In the present study, global analysis of gene expression and quantitative PCR of relevant genes showed that hypoxia provokes a general adaptive response in neuroblastoma cells and confirm loss of the neuronal phenotype and gain of stem-cell characteristics. Of the approximately 17,000 genes and ESTs analyzed, 199 were consistently upregulated and 36 were downregulated more than 2-fold by hypoxia. As anticipated, several genes involved in glucose and iron metabolism and neovascularization were upregulated, the latter group we here show to include the gene encoding chromogranin C and its cleavage product, secretoneurin, a vascular smooth muscle cell mitogen. We also observed upregulation of genes implicated in cell survival and growth, such as vascular endothelial growth factor (VEGF), neuropilin 1, adrenomedullin, and IGF-2. Several metallothioneins, which are linked to tumor drug resistance, were upregulated, whereas the expression of MDR1 decreased. In hypoxic neuroblastoma cells, proneuronal lineage specifying transcription factors, and their dimerization partner E2-2, were downregulated, whereas their inhibitors Id2 and HES-1 were induced, providing a molecular mechanism for the hypoxia-provoked dedifferentiation of neuroblastoma cells.
Jögi
Annika
A
Department of Laboratory Medicine, Division of Molecular Medicine, University Hospital MAS, Lund University, S-205 02 Malmö, Sweden.
Vallon-Christersson
Johan
J
Holmquist
Linda
L
Axelson
Håkan
H
Borg
Ake
A
Påhlman
Sven
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D053607:Adrenomedullin; D002454:Cell Differentiation; D002455:Cell Division; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D006801:Humans; D007150:Immunohistochemistry; D051797:Inhibitor of Differentiation Protein 2; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008954:Models, Biological; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D039942:Neuropilin-1 / Q000235:genetics; D010455:Peptides / Q000235:genetics; D012097:Repressor Proteins; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000235:genetics; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004268:DNA-Binding Proteins; D005819:Genetic Markers; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D010455:Peptides; D012097:Repressor Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; D053607:Adrenomedullin; D007335:Insulin-Like Growth Factor II