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Relaxation of IGF2 and KIP2 imprinting in Wilms tumours and other urogenital tumours

肾母细胞瘤和其他泌尿生殖肿瘤中 IGF2 和 KIP2 印记的松弛

基本信息

批准号：
10670135
负责人：
TANIGUCHI Takanobu
金额：
$ 2.24万
依托单位：
Fukui Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670135/
关键词：
Wilms tumour urogenital tumour imprinting KIP2 IGF2 膀胱癌前立腺癌精巣腫瘍細胞周期 kip2

项目摘要

Relaxation of IGF2 imprinting occurs in Wilms tumours and many other solid tumours, but the mechanism of loss of imprinting (LOI) has not yet been determined. To investigate the role of altered DNA methylation in relaxation of genomic imprinting, we have examined the pattern of DNA methylation within the complete human IGF2 gene and KIP2 gene in Wilms tumours and other urogenital tumours that have either lost or retained IGF2 imprinting. Relaxation of imprinting involves loss of the maternal imprint from the three imprinted IGF2 promoters (P2, P3 and P4) which are clustered together within a CpG island. Methylation analysis of the IGF2 CpG island showed that these three imprinted promoters were unmethylated in all Wilms tumours and in the normal kidney. However, this analysis identified a region of allele specific DNA methylation on the maternal IGF2 allele between exons 2 and 3, upstream of the imprinted IGF2 promoters, that is present in tumours with normal imprinted IGF2 expression, but lost in tumours with relaxation of imprinting. In addition a boundary of DNA methylation was found at two ALU repeat elements in intron 1 that may be involved in the imprinting process. In contrast, KIP2 gene was entirely unmethylated in all tumours and normal kidneys. From these results we postulate the existence of an upstream cis-acting methylation center in the human IGF2 that may co-ordinately control expression and imprinting from the down stream promoters. However, KIP2 gene seems to be under independent regulation of IGF2/H19 imprinting domain.

IGF 2印迹的松弛发生在肾母细胞瘤和许多其他实体瘤中，但印迹丢失（LOI）的机制尚未确定。为了研究DNA甲基化改变在基因组印记松弛中的作用，我们研究了肾母细胞瘤和其他泌尿生殖系统肿瘤中完整的人IGF 2基因和KIP 2基因内的DNA甲基化模式，这些肿瘤已经失去或保留了IGF 2印记。印记的松弛涉及来自三个印记IGF 2启动子（P2、P3和P4）的母体印记的损失，所述印记IGF 2启动子在CpG岛内聚集在一起。IGF 2 CpG岛的甲基化分析表明，这三个印迹启动子在所有肾母细胞瘤和正常肾脏中未甲基化。然而，这项分析确定了一个区域的等位基因特异性DNA甲基化的母系IGF 2等位基因之间的外显子2和3，上游的印记IGF 2的启动子，这是目前在肿瘤与正常的印记IGF 2表达，但失去了在肿瘤中的印记松弛。此外，在内含子1的两个ALU重复元件处发现了DNA甲基化的边界，这可能参与了印迹过程。相反，KIP 2基因在所有肿瘤和正常肾脏中完全未甲基化。从这些结果中，我们假设存在一个上游顺式作用甲基化中心的人IGF 2，可以协调控制表达和印记从下游启动子。而KIP 2基因似乎受IGF 2/H19印迹结构域的独立调控。