Mechanisms in Wilms Tumorigenesis

肾母细胞瘤发生机制

• 批准号: 6802921
• 负责人: Bryan R. G. Williams
• 金额: $ 27.64万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-23 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6802921
• 关键词: Wilms' tumor; carcinogenesis; clinical research; complementary DNA; developmental genetics; embryo neoplasm; gene induction /repression; growth factor; immunoprecipitation; kidney; laboratory mouse; mammalian embryology; microarray technology; molecular cloning; neoplasm /cancer genetics; nephrogenesis; recombinant proteins; tumor suppressor genes; tumor suppressor proteins

Wilms tumor is an embryonal kidney cancer of children that has been linked to molecular genetic abnormalities on the short arm of chromosome 11. This tumor is associated with anomalies in the urogenitary system and a shared genetic origin has become evident from the cloning and characterization of the WT1 locus by ourselves and others. WT1 is restricted in expression to the condensing metanephric mesenchyme or developing glomeruli. Thus it must respond to induction signals following interaction of the metanephric mesenchyme and the epithelial ureteric bud and likely regulate the expression of other genes involved in differentiation and morphogenesis. The long term objective of this project is to determine how the WT1 regulates this process by identifying WT1-target genes and defining their role in nephrogenesis and tumorigenesis. These objectives will be achieved by pursuing the following specific aims. To test the hypothesis that WT1 both activates and represses target genes to regulate nephrogenesis in Aim one we will characterize genes identified as potential WT1 targets from GeneChip analyses by studying their promoters, examining their expression in Wilms tumors and during nephrogenesis in vitro and in vivo. In aim two we will use chromatin precipitation to identify genes that are direct transcriptional targets for WT1. In aim three we will modulate WT1 and p53 expression in a Wilms tumor cell line and determine effects on transcript profiles. We will also develop kidney specific cDNA arrays and methods for specifically ablating selective transcripts. The proposed studies promise to provide new insights into the role of WT1 as a transcriptional regulator and to lead to the identification of novel genes involved in nephrogenesis and Wilms tumorigenesis.

肾母细胞瘤是一种儿童胚胎肾癌，与 11 号染色体短臂上的分子遗传异常有关。这种肿瘤与泌尿生殖系统异常有关，并且从该肿瘤的克隆和表征中可以明显看出其共同的遗传起源。我们自己和其他人的 WT1 轨迹。 WT1 的表达仅限于浓缩后肾间质或发育中的肾小球。 因此，它必须对后肾间充质和输尿管上皮芽相互作用后的诱导信号作出反应，并可能调节参与分化和形态发生的其他基因的表达。 该项目的长期目标是通过识别 WT1 靶基因并定义它们在肾发生和肿瘤发生中的作用来确定 WT1 如何调节这一过程。 这些目标将通过追求以下具体目标来实现。 为了测试 WT1 在 Aim one 中激活和抑制靶基因来调节肾发生的假设，我们将通过研究它们的启动子、检查它们在肾母细胞瘤中以及体外和体内肾发生过程中的表达来表征基因芯片分析中确定为潜在 WT1 靶标的基因。 在目标二中，我们将使用染色质沉淀来识别作为 WT1 直接转录靶标的基因。 在目标三中，我们将调节 Wilms 肿瘤细胞系中的 WT1 和 p53 表达，并确定对转录谱的影响。 我们还将开发肾脏特异性 cDNA 阵列和用于特异性消融选择性转录本的方法。 拟议的研究有望为 WT1 作为转录调节因子的作用提供新的见解，并导致鉴定涉及肾发生和肾母细胞瘤发生的新基因。

项目成果

Vascular endothelial growth factor (VEGF) is suppressed in WT1-transfected LNCaP cells.

WT1 转染的 LNCaP 细胞中血管内皮生长因子 (VEGF) 受到抑制。

• 发表时间: 2006
• 作者: Graham, Kylie;Li, Wenliang;Williams, Bryan R G;Fraizer, Gail
• 通讯作者: Fraizer, Gail

A gene expression signature for relapse of primary wilms tumors.

原发性肾母细胞瘤复发的基因表达特征。

• 发表时间: 2005-04-01
• 作者: Li, Wenliang;Kessler, Patricia;Yeger, Herman;Alami, Jennifer;Reeve, Anthony E;Heathcott, Rosemary;Skeen, Jane;Williams, Bryan R G
• 通讯作者: Williams, Bryan R G

Differential expression of E-cadherin and beta catenin in primary and metastatic Wilms's tumours.

E-钙粘蛋白和β连环蛋白在原发性和转移性肾母细胞瘤中的差异表达。

• 发表时间: 2003-08
• 作者: Alami, J;Williams, B R;Yeger, H
• 通讯作者: Yeger, H

Derivation and characterization of a Wilms' tumour cell line, WiT 49.

Wilms 肿瘤细胞系 WiT 49 的衍生和表征。

• 发表时间: 2003-11-10
• 影响因子: 6.4
• 作者: Alami, Jennifer;Williams, Bryan R;Yeger, Herman
• 通讯作者: Yeger, Herman

Transcript profiling of Wilms tumors reveals connections to kidney morphogenesis and expression patterns associated with anaplasia.

肾母细胞瘤的转录谱揭示了与肾形态发生和与退行性变相关的表达模式的联系。

• 发表时间: 2005-01-13
• 作者: Li, Wenliang;Kessler, Patricia;Williams, Bryan R G
• 通讯作者: Williams, Bryan R G