Hypoxia-inducible expression of tumor-associated carbonic anhydrases.

Journal article

The transcriptional complex hypoxia-inducible factor-1 (HIF-1) has emerged as an important mediator of gene expression patterns in tumors, although the range of responding genes is still incompletely defined. Here we show that the tumor-associated carbonic anhydrases (CAs) are tightly regulated by this system. Both CA9 and CA12 were strongly induced by hypoxia in a range of tumor cell lines. In renal carcinoma cells that are defective for the von Hippel-Lindau (VHL) tumor suppressor, up-regulation of these CAs is associated with loss of regulation by hypoxia, consistent with the critical function of pVHL in the regulation of HIF-1. Further studies of CA9 defined a HIF-1-dependent hypoxia response element in the minimal promoter and demonstrated that tight regulation by the HIF/pVHL system was reflected in the pattern of CA IX expression within tumors. Generalized up-regulation of CA IX in VHL-associated renal cell carcinoma contrasted with focal perinecrotic expression in a variety of non-VHL-associated tumors. In comparison with vascular endothelial growth factor mRNA, expression of CA IX demonstrated a similar, although more tightly circumscribed, pattern of expression around regions of necrosis and showed substantial although incomplete overlap with activation of the hypoxia marker pimonidazole. These studies define a new class of HIF-1-responsive gene, the activation of which has implications for the understanding of hypoxic tumor metabolism and which may provide endogenous markers for tumor hypoxia.

Authors: Wykoff, C; Beasley, N; Watson, P; Turner, K; Pastorek, J

• Publication status: Published
• Journal: Cancer research
• Volume: 60
• Issue: 24
• Pages: 7075-7083
• Publication date: 2000-12-01
• EISSN: 1538-7445
• ISSN: 0008-5472
• Language: English
• Keywords: Models, Genetic; DNA-Binding Proteins; Urinary Bladder Neoplasms; Kidney Neoplasms; Promoter Regions, Genetic; Immunoblotting; Endothelial Growth Factors; Necrosis; Nitroimidazoles; RNA; Immunohistochemistry; Hypoxia-Inducible Factor 1, alpha Subunit; Skin Neoplasms; RNA, Messenger; Vascular Endothelial Growth Factors; Carcinoma, Renal Cell; Carcinoma; Oxygen; Carbonic Anhydrases; Transcription Factors; Lymphokines; In Situ Hybridization; Plasmids; Humans; Hypoxia-Inducible Factor 1; Nuclear Proteins; Anoxia; Up-Regulation; Vascular Endothelial Growth Factor A; Genes, Reporter; Blotting, Western; Tumor Cells, Cultured; Radiation-Sensitizing Agents