Candidate genes for the hypoxic tumor phenotype.
In this study, we have analyzed changes induced by hypoxia at the transcriptional level of genes that could be responsible for a more aggressive phenotype. Using a series of DNA array membranes, we identified a group of hypoxia-induced genes that included plasminogen activator inhibitor-1 (PAI-1), insulin-like growth factor-binding protein 3 (IGFBP-3), endothelin-2, low-density lipoprotein receptor-related protein (LRP), BCL2-interacting killer (BIK), migration-inhibitory factor (MIF), matrix metalloproteinase-13 (MMP-13), fibroblast growth factor-3 (FGF-3), GADD45, and vascular endothelial growth factor (VEGF). The induction of each gene was confirmed by Northern blot analysis in two different squamous cell carcinoma-derived cell lines. We also analyzed the kinetics of PAI-1 induction by hypoxia in more detail because it is a secreted protein that may serve as a useful molecular marker of hypoxia. On exposure to hypoxia, there was a gradual increase in PAI-1 mRNA between 2 and 24 h of hypoxia followed by a rapid decay after 2 h of reoxygenation. PAI-1 levels were also measured in the serum of a small group of head and neck cancer patients and were found to correlate with the degree of tumor hypoxia found in these patients.
Koong
A C
AC
Department of Radiation Oncology, Stanford University School of Medicine, California 94305-5468, USA.
Denko
N C
NC
Hudson
K M
KM
Schindler
C
C
Swiersz
L
L
Koch
C
C
Evans
S
S
Ibrahim
H
H
Le
Q T
QT
Terris
D J
DJ
Giaccia
A J
AJ
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D015687:Cell Hypoxia; D016228:Endothelial Growth Factors / Q000235:genetics; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics; D008222:Lymphokines / Q000235:genetics; D008565:Membrane Proteins; D051379:Mice; D024101:Mitochondrial Proteins; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D016228:Endothelial Growth Factors; D018972:Insulin-Like Growth Factor Binding Protein 3; D008222:Lymphokines; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D017395:Plasminogen Activator Inhibitor 1; D011506:Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors