Said Harun M, Staab Adrian, Hagemann Carsten, Vince Giles H, Katzer Astrid, Flentje Michael, Vordermark Dirk
Department of Radiation Oncology, University of Wuerzburg, Josef-Schneider-Strasse 11, 97080 Wuerzburg, Germany.
J Neurooncol. 2007 Jan;81(1):27-38. doi: 10.1007/s11060-006-9205-2. Epub 2006 Aug 31.
The hypoxia-inducible enzyme carbonic anhydrase IX (CA IX) has recently been discussed as a surrogate marker of tumor hypoxia, an indicator of prognosis and a potential therapeutic target in malignant glioma. To characterize patterns of expression of CA IX in human malignant glioma cells, we studied CA IX protein, CA9 mRNA and hypoxia-inducible factor-1alpha (HIF-1alpha) protein levels in U87-MG, U251, U373 and GaMG cells exposed to in vitro hypoxia (1, 6 or 24 h at 5%, 1% or 0.1% O(2)). All cell lines displayed a strong hypoxic induction of CA9 mRNA in response to prolonged severe hypoxia with cell-line specific patterns at moderate to mild hypoxia and shorter treatment times. Only U87-MG exhibited a strong constitutive, normoxic expression of CA IX protein without a detectable change under hypoxia. In U251 and GaMG cell lines, a marked induction of CA IX protein in response to severe hypoxia was seen. CA IX changes under severe hypoxia and the inhibitory effect of the glycolysis inhibitor iodoacetate (IAA, 50 microM) on hypoxic CA IX overexpression were paralleled by the results for HIF-1alpha protein. Therefore, immunohistochemical CA IX staining in human malignant glioma specimens can result from low oxygen concentrations or constitutive, oncogene-related, overexpression both of which may be prognostically relevant.
缺氧诱导酶碳酸酐酶IX（CA IX）最近被视为肿瘤缺氧的替代标志物、预后指标以及恶性胶质瘤潜在的治疗靶点。为了明确人恶性胶质瘤细胞中CA IX的表达模式，我们研究了暴露于体外缺氧环境（5%、1%或0.1% O₂下1、6或24小时）的U87-MG、U251、U373和GaMG细胞中的CA IX蛋白、CA9 mRNA以及缺氧诱导因子-1α（HIF-1α）蛋白水平。所有细胞系在长时间严重缺氧时均表现出强烈的CA9 mRNA缺氧诱导，在中度至轻度缺氧及较短处理时间时呈现细胞系特异性模式。只有U87-MG表现出CA IX蛋白的强烈组成型常氧表达，在缺氧状态下无明显变化。在U251和GaMG细胞系中，可观察到严重缺氧时CA IX蛋白的显著诱导。严重缺氧时CA IX的变化以及糖酵解抑制剂碘乙酸盐（IAA，50 μM）对缺氧诱导的CA IX过表达的抑制作用与HIF-1α蛋白的结果相似。因此，人恶性胶质瘤标本中的免疫组化CA IX染色可能源于低氧浓度或组成型、与癌基因相关的过表达，这两者在预后方面可能都具有相关性。
