HIF activation identifies early lesions in VHL kidneys: Evidence for site-specific tumor suppressor function in the nephron
HIF activation identifies early lesions in VHL kidneys: Evidence for site-specific tumor suppressor function in the nephron
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DOI：
10.1016/s1535-6108(02)00071-5
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发表时间：
2002-06-01
期刊：
影响因子：
50.3
通讯作者：
Maxwell, PH
中科院分区：
文献类型：
--
作者：
Mandriota, SJ;Turner, KJ;Maxwell, PH
von Hippel-Lindau（VHL）基因突变与遗传性和散发性肾透明细胞癌相关。VHL在调节低氧诱导因子-1（HIF-1）的泛素连接酶复合物中起作用，但这种功能与癌症发展之间的联系尚不清楚。在这里，我们表明，在VHL疾病患者的肾脏，HIF激活是一个早期事件发生在形态正常的单细胞内的肾小管。相比之下，发育不良病变，囊性病变和肿瘤表现出额外的机制，放大HIF激活的证据。检测具有组成性HIF激活的细胞鉴定了大量先前未识别的VHL失活灶。在近端小管，这些几乎完全是单细胞的，而多细胞灶几乎只出现在远端肾单位。
Mutations in the von Hippel-Lindau (VHL) gene are associated with hereditary and sporadic clear cell renal carcinoma. VHL acts in a ubiquitin ligase complex regulating hypoxia-inducible factor-1 (HIF-1), but the link between this function and cancer development is unclear. Here we show that in the kidneys of patients with VHL disease, HIF activation is an early event occurring in morphologically normal single cells within the renal tubules. In comparison, dysplastic lesions, cystic lesions, and tumors showed evidence of additional mechanisms that amplify HIF activation. Detection of cells with constitutive HIF activation identified a large number of previously unrecognized foci of VHL inactivation. In proximal tubules these were almost entirely unicellular, whereas multicellular foci were almost exclusively seen in the distal nephron.