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首页> 外文期刊>Molecular Cancer >The Wilms’ tumor gene (WT1) regulates E-cadherin expression and migration of prostate cancer cells
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The Wilms’ tumor gene (WT1) regulates E-cadherin expression and migration of prostate cancer cells

机译：威尔姆斯的肿瘤基因（WT1）调节E-钙粘蛋白的表达和前列腺癌细胞的迁移

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Background One key step in the development of prostate cancer ( PCa ) metastasis is the loss of E-cadherin expression associated with increased cellular motility and tumor invasion. This loss of E-cadherin expression is also required during normal embryogenesis and similar transcriptional repressors have been identified in both processes. We have previously reported the presence of one such transcription factor, WT1 in high Gleason grade prostate tumor tissues, and its absence in non-neoplastic or benign prostatic hyperplasia tissues. Results To better understand the effect of WT1 on E-cadherin expression and migration of PCa cells we quantified WT1 and E-cadherin mRNA levels in normal prostate epithelial and PCa cell lines with varying migratory potential. In WT1 transfected cells E-cadherin transcript levels were decreased, while they were increased in siWT1-RNA transfected PCa cells, suggesting that elevated WT1 expression was sufficient to dampen E-cadherin levels and potentially enhance migratory ability. To delineate the mechanism of WT1-mediated repression of E-cadherin, potential WT1 binding sites were tested in vitro and in vivo binding of WT1 to the E-cadherin promoter in the chromatin of LNCaP and PC3 cells was assessed by Chromatin Immunoprecipitation . The effect of WT1 binding was measured in reporter assays; in PC3 and DU145 cells WT1 decreased the activity of the proximal E-cadherin promoter. Using site-directed mutagenesis, a newly identified WT1 binding site located 146 bp from the transcription start site was shown to be required for this repression by WT1. Transwell migration and wound healing assays revealed that in LNCaP cells with low migratory potential, over-expression of WT1 was sufficient to enhance migration, conversely, in the highly migratory PC3 cells silencing of WT1 decreased migration. Conclusions These findings suggested that WT1 expression in high grade prostate cancer may contribute to migration and metastasis. Thus, in prostate cancer WT1 may function as a novel oncogene facilitating development of the lethal metastatic phenotype.
机译：背景技术前列腺癌（PCa）转移发展的一个关键步骤是E-钙粘蛋白表达的丧失与细胞运动性增加和肿瘤浸润有关。 E-钙粘着蛋白表达的这种丧失在正常的胚胎发生过程中也是必需的，并且在两个过程中都已经确定了类似的转录阻遏物。先前我们已经报道了在高格里森级前列腺肿瘤组织中存在一种这样的转录因子WT1，在非肿瘤性或良性前列腺增生组织中不存在这种转录因子。结果为了更好地了解WT1对PCa细胞E-钙粘蛋白表达和迁移的影响，我们对正常前列腺上皮和PCa细胞系中具有不同迁移潜能的WT1和E-cadherin mRNA水平进行了定量。在WT1转染的细胞中，E-cadherin转录水平降低，而在siWT1-RNA转染的PCa细胞中，E-cadherin转录水平升高，这表明升高的WT1表达足以抑制E-cadherin的水平并可能增强迁移能力。为了描述WT1介导的E-钙粘蛋白抑制的机制，在体外测试了潜在的WT1结合位点，并通过染色质免疫沉淀法评估了WT1与LNCaP和PC3细胞染色质中E-钙粘蛋白启动子的结合。 WT1结合的作用在报道基因分析中进行了测定。在PC3和DU145细胞中，WT1降低了近端E-钙粘蛋白启动子的活性。使用定点诱变，新确定的距离转录起始位点146 bp的WT1结合位点被证明是WT1抑制所必需的。 Transwell迁移和伤口愈合试验表明，在迁移潜力低的LNCaP细胞中，WT1的过表达足以增强迁移，相反，在迁移高度的PC3细胞中，WT1的沉默降低了迁移。结论这些发现表明，WT1在高级别前列腺癌中的表达可能与迁移和转移有关。因此，在前列腺癌中，WT1可能起促进致死转移表型发展的新型致癌基因的作用。

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