期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 13, 期 11-12, 页码 4522-4531出版社
WILEY
DOI: 10.1111/j.1582-4934.2008.00574.x
关键词
WT1; HOXA10; uterine cancer; ovarian cancer
资金
- NIH [HD036887, HD052668]
Homeobox genes encode transcription factors that dictate developmental identity, including that of the Mullerian tract. These genes also direct differential Mullerian transformation of the ovarian cancer cells. The homeobox gene HOXA10 controls uterine organogenesis during embryonic development and similarly is expressed in endometroid epithelial ovarian cancer. Here we confirmed aberrant regulation of HOXA10 expression in epithelial uterine and ovarian carcinomas. We identified a HOXA10 epithelial regulatory element containing an enhancer that drove HOXA10 expression specifically in gynaecologic epithelium. We further identified an adjoining dominant repressor element that restricted regulation by the epithelial enhancer to a subset of epithelial cell types. The repressor contained two functional WT1 binding sites. We identified a strong inverse correlation between HOXA10 expression and that of the Wilms' Tumour 1 (WT1) gene in multiple benign and malignant gynaecologic tissues, suggesting functionality of the WT1 sites in the repressor. Mutation of the two WT1 binding sites abolished WT1 binding to the element as well as the ability to affect epithelial enhancer activity in reporter assays. Similarly, decreased expression of WT1 using siRNA prevented repressor activity. The Mullerian phenotype seen in ovarian cancer is dependent on gain of HOX gene expression secondary to the loss of WT1-mediated HOX repression. This suggests that Gynaecologic epithelial histologic type is regulated by WT1 expression through its selective repression of HOX genes.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据