The von Hippel-Lindau tumor suppressor gene and kidney cancer
The von Hippel-Lindau tumor suppressor gene and kidney cancer
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DOI：
10.1158/1078-0432.ccr-sup-040025
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发表时间：
2004-09-15
影响因子：
11.5
通讯作者：
Kaelin, WG
中科院分区：
文献类型：
--
作者：
Kaelin, WG
位于3p25染色体上的von Hippel-Lindau肿瘤抑制基因（VHL）在50%的散发性透明细胞肾细胞癌中发生突变或沉默。种系VHL突变可引起VHL疾病，其特点是血管肿瘤（血管母细胞瘤）和肾细胞癌的风险增加。在这种情况下，VHL失活引起癌前肾囊肿。这些囊肿转化为肾细胞癌可能需要额外的基因改变。VHL-/-肾细胞癌中VHL功能的恢复足以在体内抑制肿瘤发生。基于这些和其他数据，VHL似乎是肾细胞癌发展的关键把关人。VHL基因产物pVHL是E3泛素连接酶的底物识别模块，该连接酶针对缺氧诱导因子（HIF）在氧气存在下进行破坏。缺氧细胞或缺乏pVHL的细胞会积累高水平的HIF， HIF会激活多种基因的转录，包括血管内皮生长因子、血小板源性生长因子B和转化生长因子α。在肾细胞癌裸鼠异种移植实验中，我们已经证明抑制HIF是pVHL抑制肿瘤的必要和充分条件。这为使用HIF抑制剂或其下游靶点治疗VHL-/-肾细胞癌提供了理论依据。然而，VHL疾病的基因型-表型相关性表明，pVHL除HIF外还有靶点。阐明这些靶点将提供pVHL如何抑制肿瘤生长的更完整的图像。
The von Hippel-Lindau tumor suppressor gene (VHL), which resides on chromosome 3p25, is mutated or silenced in >50% of sporadic clear cell renal cell carcinomas. Germline VHL mutations give rise to VHL disease, which is characterized by an increased risk of blood vessel tumors (hemangioblastomas) and renal cell carcinomas. In this setting, VHL inactivation gives rise to premalignant renal cysts. Additional genetic alterations are presumably required for conversion of these cysts to renal cell carcinomas. Restoration of VHL function in VHL-/- renal cell carcinomas is sufficient to inhibit tumorigenesis in vivo. On the basis of these and other data, VHL appears to be a critical gatekeeper with respect to the development of renal cell carcinoma. The VHL gene product, pVHL, is the substrate recognition module of an E3 ubiquitin ligase that targets the hypoxia-inducible factor (HIF) for destruction in the presence of oxygen. Hypoxic cells, or cells lacking pVHL, accumulate high levels of HIF, which activates the transcription of a variety of genes, including vascular endothelial growth factor, platelet-derived growth factor B, and transforming growth factor alpha. We have demonstrated that inhibition of HIF is necessary and sufficient for tumor suppression by pVHL in renal cell carcinoma nude mouse xenograft assays. This provides a rationale for treating VHL-/- renal cell carcinoma with inhibitors of HIF or its downstream targets. Genotype-phenotype correlations in VHL disease suggest, however, that pVHL has targets in addition to HIF. Elucidating these targets should provide a more complete picture of how pVHL suppresses tumor growth.