Nuclear expression of hypoxia-inducible factor-1α in clear cell renal cell carcinoma is involved in tumor progression
Nuclear expression of hypoxia-inducible factor-1α in clear cell renal cell carcinoma is involved in tumor progression
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DOI：
10.1097/pas.0b013e318094fed8
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发表时间：
2007-12-01
影响因子：
5.6
通讯作者：
Cavazzana, Andrea
中科院分区：
文献类型：
--
作者：
Di Cristofano, Claudio;Minervini, Andrea;Cavazzana, Andrea
目的：肾透明细胞癌（cc-RCC）中最常见的基因组异常是VHL基因的失活。pVHL 19是促进低氧诱导因子-1 α（HIF-1 α）的蛋白体降解的连接酶; pVHL 30与微管相关。VHL直接和通过HIF-1 α激活发挥其致癌作用。TNM分类不能确定囊内cc-RCC的正确预后评估。VHL/HIF-1 α信号通路的核质转运可能有助于了解肾癌发生的分子机制。本研究分析了VHL/HIF-1 α蛋白在一个大的系列的囊内cc-RCC，其表达和细胞定位与projective.Materials和方法：两个抗pVHL（克隆Ig 32和Ig 33）和1抗HIF-1 α被用于组织芯片从136囊内cc-RCC（平均随访：74个月）。克隆32识别两种pVHL，而克隆33仅识别pVHL 30。结果与临床病理变量和肿瘤特异性生存（TSS）相匹配。结果：所有抗体在最大部分病例中均呈强细胞质阳性，与HIF-1 α的强核定位相关。所有pVHL阴性病例均与HIF-1 α高表达相关。pVHL阴性和HIF-1 α核阳性与较短TSS显著相关。在多变量分析中，pVHL阴性和HIF-1 α核表达是TSS的独立预测因子。结论：蛋白质的定位与其作用和假设的肿瘤分子通路相匹配。VHL/HIF-1 α改变与预后的相关性证实了其分子途径及其产物的细胞运输在肾癌发病机制中的相关性。
Objectives: The most frequent genomic abnormality in clear cell renal cell carcinoma (cc-RCC) is inactivation of Von Hippel-Lindau gene (VHL). pVHL 19 is a ligase promoting proteosomal degradation of hypoxia-inducible factor-lalfa (HIF-1 alpha); pVHL30 is associated with microtubules. VHL exert its oncogenetic action both directly and through HIF-1 alpha activation. TNM classification is unable to define a correct prognostic evaluation of intracapsular cc-RCC. The nucleo-cytoplasmic trafficking in VHL/HIF-1 alpha pathway could be relevant in understanding the molecular pathogenesis of renal carcinogenesis. This study analyzes VHL/HIF-1 alpha proteins in a large series of intracapsular cc-RCCs, correlating their expression and cellular localization with prognosis.Materials and Methods: Two anti-pVHL (clones Ig32 and Ig33) and 1 anti-HIF-1 alpha were used on tissue microarrays from 136 intracapsular cc-RCCs (mean follow-up: 74mo). Clone 32 recognizes both pVHLs, whereas clone 33 only pVHL30. Results were matched with clinicopathologic variables and tumor-specific survival (TSS).Results: A strong cytoplasmic positivity was found for all antibodies in the largest part of cases, associated to a strong nuclear localization in the case of HIF-1 alpha. All pVHL-negative cases were associated with high HIF-1 alpha expression. pVHL negativity and HIF-1 alpha nuclear positivity significantly correlated with shorter TSS. In multivariate analysis both pVHL negativity and HIF-1 alpha nuclear expression were independent predictors of TSS.Conclusions: The localization of the proteins well matches with their role and with the supposed tumor molecular pathways. The correlation with prognosis of VHL/HIF-1 alpha alterations confirms the relevance of their molecular pathway and of the cellular trafficking of their products in the pathogenesis of renal cancer.