Loss of VHL and Hypoxia Provokes PAX2 Up-Regulation in Clear Cell Renal Cell Carcinoma
Loss of VHL and Hypoxia Provokes PAX2 Up-Regulation in Clear Cell Renal Cell Carcinoma
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DOI：
10.1158/1078-0432.ccr-08-2779
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发表时间：
2009-05-15
影响因子：
11.5
通讯作者：
Moch, Holger
中科院分区：
文献类型：
--
作者：
Luu, Van-Duc;Boysen, Gunther;Moch, Holger
目的：配对盒基因2（PAX 2）编码一种转录因子，该因子在肾发生期间上调，并在肾小球、近端和远端小管的成熟上皮中变得沉默。在透明细胞肾细胞癌（ccRCC）中经常观察到PAX 2的再活化，这是一种以von Hippel-Lindau（VHL）肿瘤抑制功能丧失为特征的肿瘤类型。在ccRCC中PAX 2表达的调节是未知的。实验设计：我们应用报告基因测定来研究PAX 2启动子调节。此外，在VHL野生型和突变背景中，在常氧和低氧条件下在ccRCC细胞系中测定PAX 2表达。PAX 2的表达也在831人ccRCC和相关的缺氧诱导因子a（HIF α）和临床parameters.Results：在这里，我们表明，VHL蛋白（pVHL）功能和缺氧的损失导致强PAX 2的再表达。使用荧光素酶报告基因测定，没有得到诱导，尽管在PAX 2的启动子中确定了6个缺氧反应元件基序。综合免疫组化分析显示，在ccRCC患者中，PAX 2、HIF 1 α和HIF 2 α靶CCND 1表达模式之间存在显著相关性。值得注意的是，PAX 2表达与早期、分化良好的ccRCC高度相关，因此与更好的临床结果高度相关（均P < 0.0001）。另外的分析表明，PAX 2阻遏物WT 1和癌症相关的低甲基化是不重要的转录调控PAX 2在ccRCC.Conclusion：我们的结论是，在ccRCC中，PAX 2的再激活是由HIF依赖的机制pVHL损失。
Purpose: The paired box gene 2, PAX2, encodes for a transcription factor that is up-regulated during nephrogenesis and becomes silenced in mature epithelium of the glomeruli, the proximal, and distal tubules. Reactivation of PAX2 has been frequently observed in clear cell renal cell carcinoma (ccRCC), a tumor type characterized by loss of von Hippel-Lindau (VHL) tumor suppressor function. The regulation of PAX2 expression in ccRCC is unknown.Experimental Design: We applied reporter gene assays to investigate PAX2 promoter regulation. Furthermore, PAX2 expression was determined in ccRCC cell lines under normoxic and hypoxic condition in a VHL wild-type and mutated background. PAX2 expression was also assessed in 831 human ccRCC and correlated with hypoxia-inducible factor a (HIF alpha) and clinical parameters.Results: Here, we show that both loss of VHL protein (pVHL) function and hypoxia leads to strong PAX2 reexpression. Using luciferase reporter gene assays, no induction was obtained in spite of six hypoxia response element motifs identified in the promoter of PAX2. Comprehensive immunohistochemical analyses showed significant correlations between PAX2, HIF1 alpha, and HIF2 alpha-target CCND1 expression patterns in ccRCC patients. Notably, PAX2 expression was highly associated with early-stage, well-differentiated ccRCC and, consequently, better clinical outcome (P < 0.0001 each). Additional analyses indicated that PAX2 repressor WT1 and cancer-linked hypomethylation are not important for transcriptional regulation of PAX2 in ccRCC.Conclusion: We conclude that in ccRCC, PAX2 reactivation is driven by HIF-dependent mechanisms following pVHL loss.