Expression of hypoxia-lnducible cell-surface transmembrane carbonic anhydrases in human cancer
Expression of hypoxia-lnducible cell-surface transmembrane carbonic anhydrases in human cancer
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DOI：
10.1016/s0002-9440(10)64038-2
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发表时间：
2001-03-01
影响因子：
6
通讯作者：
Stanbridge, EJ
中科院分区：
文献类型：
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作者：
Ivanov, S;Liao, SY;Stanbridge, EJ
细胞外酸性pH值是恶性表型的基本特征。在von Hippel-Lindau （VHL）缺陷肿瘤中，由于缺乏pVHL，细胞表面跨膜碳酸酐酶（CA） CA9和CA12基因过表达。我们推测这些酶可能参与维持肿瘤细胞外的酸性pH值，从而为肿瘤的生长和扩散提供有利的环境。利用Northern blot分析和特异性抗体免疫染色，我们分析了CA9和CA12基因及其产物在大量癌细胞系、新鲜和存档肿瘤标本和正常人体组织中的表达。在低氧条件下也分析了培养细胞的表达。CA IX和CA XII在正常成人组织中的表达仅在高度特化的细胞中检测到，并且在大多数组织中它们的表达并不重叠。从87种癌细胞系和18种肿瘤中分离的RNA样本分析显示，多种癌症中CA9和CA12的高至中等水平表达。免疫组织化学显示这些酶在各种正常组织和多种常见上皮肿瘤类型中高表达。免疫染色主要见于细胞膜表面。在肿瘤和培养的肿瘤细胞缺氧条件下，这两个基因的表达均被显著诱导。我们得出的结论是，细胞表面跨膜碳酸酐酶CA IX和CA XII在许多肿瘤中过度表达，这表明这是癌细胞的共同特征，可能是肿瘤进展所必需的。这些酶可能通过维持细胞外酸性pH值和帮助癌细胞生长和转移来促进肿瘤微环境。我们的研究表明，在人类肿瘤中，缺氧、细胞外酸化和诱导或增强这些酶的表达之间存在重要的因果关系。
An acidic extracellular pH is a fundamental property of the malignant phenotype. In von Hippel-Lindau (VHL)-defective tumors the cell surface transmembrane carbonic anhydrase (CA) CA9 and CA12 genes are overexpressed because of the absence of pVHL. We hypothesized that these enzymes might be involved in maintaining the extracellular acidic pH in tumors, thereby providing a conducive environment for tumor growth and spread. Using Northern blot analysis and immunostaining with specific antibodies we analyzed the expression of CA9 and CA12 genes and their products in a large sample of cancer cell lines, fresh and archival tumor specimens, and normal human tissues. Expression was also analyzed in cultured cells under hypoxic conditions. Expression of CA IX and CA XII in normal adult tissues was detected only in highly specialized cells and for most tissues their expression did not overlap. Analysis of RNA samples isolated from 87 cancer cell lines and 18 tumors revealed high-to-moderate levels of expression of CA9 and CA12 in multiple cancers. Immunohistochemistry revealed high-to-moderate expression of these enzymes in various normal tissues and multiple common epithelial tumor types. The immunostaining was seen predominantly on the cell surface membrane. The expression of both genes was markedly induced under hypoxic conditions in tumors and cultured tumor cells. We conclude that the cell surface trans-membrane carbonic anhydrases CA IX and CA XII are overexpressed in many tumors suggesting that this is a common feature of cancer cells that may be required for tumor progression. These enzymes may contribute to the tumor microenvironment by maintaining extracellular acidic pH and helping cancer cells grow and metastasize. Our studies show an important causal link between hypoxia, extracellular acidification, and induction or enhanced expression of these enzymes in human tumors.