The role of carbonic anhydrase IX overexpression in kidney cancer
The role of carbonic anhydrase IX overexpression in kidney cancer
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DOI：
10.1016/j.ejca.2005.09.011
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发表时间：
2005-12-01
影响因子：
8.4
通讯作者：
Dutcher, JP
中科院分区：
文献类型：
--
作者：
Dorai, T;Sawczuk, IS;Dutcher, JP
碳酸酐酶IX（CA IX）是一种膜同工酶，其过表达与肾透明细胞癌有关。它的过度表达主要限于癌症，因为它在相应的正常组织中不存在，使其成为潜在的癌症生物标志物。最近的几项研究表明，CA IX，除了其经典的酶活性可逆水合二氧化碳细胞外，以促进质子从细胞内到细胞外的净挤出，它也可以是一个关键的球员在细胞粘附过程的调节和参与调节细胞增殖，以响应缺氧环境，最终有助于肿瘤的进展。在这里，我们已经表明，唯一的酪氨酸部分CA IX存在于其细胞内域可以磷酸化的表皮生长因子依赖的方式，这表明它可以进入生长因子受体依赖的信号转导途径。我们的研究表明，酪氨酸磷酸化的CA IX可以与PI-3-激酶的调节亚基相互作用，有助于Akt的激活。这些研究揭示了一个积极的反馈回路，可以形成一个恶性循环的基础，可能有助于透明细胞肾癌的进展和不良预后。这些研究表明，CA IX信号传导可能是癌细胞中发生的缺氧驱动和缺氧非依赖性途径的一部分。最后，我们的研究强调需要一个更精细的策略，使用信号转导治疗，以抑制细胞表面碳酸酐酶的管理这种恶性肿瘤。(c)2005爱思唯尔有限公司保留所有权利。
Carbonic anhydrase IX (CA IX) is a membrane isoenzyme, the overexpression of which is associated with clear cell carcinoma of the kidney. Its overexpression is restricted mainly to cancer, as it is absent in corresponding normal tissues making it a potential cancer biomarker. Several recent studies have shown that CA IX, apart from its classical enzyme activity of reversibly hydrating carbon dioxide extracellularly to facilitate the net extrusion of protons from inside to outside the cell, it can also be a key player in the modulation of cell adhesion processes and participate in the regulation of cell proliferation in response to hypoxic environment to ultimately contribute to tumour progression. Here, we have shown that the sole tyrosine moiety of CA IX present in its intracellular domain can be phosphorylated in an epidermal growth factor dependent manner, suggesting that it can feed into the growth factor receptor dependent signalling pathways. Our studies suggest that the tyrosine phosphorylated CA IX can interact with the regulatory subunit of PI-3-Kinase, contributing to Akt activation. These studies have revealed a positive feed back loop that can form the basis of a vicious cycle that could contribute to the progression of clear cell renal carcinoma and poor prognosis. These studies show that CA IX signalling may be a part of both the hypoxia driven and hypoxia independent pathways that occur in the cancer cell. Finally, our studies emphasize the need for a more refined strategy using signal transduction therapeutics to inhibit the cell surface carbonic anhydrases for the management of this malignancy. (c) 2005 Elsevier Ltd. All rights reserved.