Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL
Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL
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DOI：
10.1038/nature01874
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发表时间：
2003-09-18
期刊：
影响因子：
64.8
通讯作者：
Krek, W
中科院分区：
文献类型：
--
作者：
Staller, P;Sulitkova, J;Krek, W
器官特异性转移部分由癌细胞上的趋化因子受体与靶器官中的匹配趋化因子之间的相互作用控制。例如，恶性乳腺癌细胞表达趋化因子受体CXCR 4，通常转移到富含CXCR 4特异性配体基质细胞衍生因子-1 α的器官（参考文献1）。目前还不确定一个不断发展的肿瘤细胞是如何重新编程以表达CXCR 4的，从而实现转移到特定器官的趋势。在这里，我们表明，冯Hippel-Lindau肿瘤抑制蛋白pVHL负调控CXCR 4的表达，由于其能力，目标缺氧诱导因子（HIF）在常氧条件下降解。这一过程在缺氧条件下受到抑制，导致HIF依赖性CXCR 4活化。一项对肾透明细胞癌的分析显示，在大多数情况下，VHL基因突变表现出CXCR 4强表达与肿瘤特异性生存率低相关。这些结果表明，CXCR 4在肿瘤细胞的演变过程中激活的机制，并意味着VHL失活收购的初期肿瘤细胞在肿瘤发生的早期，不仅赋予了选择性生存的优势，但也有倾向于家庭选定的器官。
Organ-specific metastasis is governed, in part, by interactions between chemokine receptors on cancer cells and matching chemokines in target organs. For example, malignant breast cancer cells express the chemokine receptor CXCR4 and commonly metastasize to organs that are an abundant source of the CXCR4-specific ligand stromal cell-derived factor-1alpha (ref. 1). It is still uncertain how an evolving tumour cell is reprogrammed to express CXCR4, thus implementing the tendency to metastasize to specific organs. Here we show that the von Hippel-Lindau tumour suppressor protein pVHL negatively regulates CXCR4 expression owing to its capacity to target hypoxia-inducible factor (HIF) for degradation under normoxic conditions. This process is suppressed under hypoxic conditions, resulting in HIF-dependent CXCR4 activation. An analysis of clear cell renal carcinoma that manifests mutation of the VHL gene in most cases revealed an association of strong CXCR4 expression with poor tumour-specific survival. These results suggest a mechanism for CXCR4 activation during tumour cell evolution and imply that VHL inactivation acquired by incipient tumour cells early in tumorigenesis confers not only a selective survival advantage but also the tendency to home to selected organs.