Candidate genes for the hypoxic tumor phenotype

In this study, we have analyzed changes induced by hypoxia at the transcrip tional level of genes that could be responsible for a more aggressive pheno type. Using a series of DNA array membranes, we identified a group of hypox ia-induced genes that included plasminogen activator inhibitor-1 (PAI-1), i nsulin-like growth factor- binding protein 3 (IGFBP-3), endothelin-2, low-d ensity 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 g rowth factor (VEGF), The induction of each gene was confirmed by Northern b lot analysis in two different squamous cell carcinoma-derived cell lines. W e also analyzed the kinetics of PAI-1 induction by hypoxia in more detail b ecause 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 r eoxygenation. 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 degr ee of tumor hypoxia found in these patients.