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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Gastrointestinal Differentiation Marker Cytokeratin 20 Is Regulated By Homeobox Gene Cdx1
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Gastrointestinal Differentiation Marker Cytokeratin 20 Is Regulated By Homeobox Gene Cdx1

机译：胃肠分化标志物细胞角蛋白20受同源盒基因Cdx1的调节。

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摘要

CDX1 is a transcription factor that plays a key role in intestinal development and differentiation. However, the downstream targets of CDX1 are less well defined than those of its close homo-logue, CDX2. We report here the identification of downstream targets of CDX1 using microarray gene-expression analysis and other approaches. Keratin 20 (KRT20), a member of the intermediate filament and a well-known marker of intestinal differentiation, was initially identified as one of the genes likely to be directly regulated by CDX1. CDX1 and KRT20 mRNA expression were significantly correlated in a panel of 38 colorectal cancer cell lines. Deletion and mutation analysis of the KRT20 promoter showed that the minimum regulatory region for the control of KRT20 expression by CDX1 is within 246 bp upstream of the KRT20 transcription start site. ChIP analysis confirmed that CDX1 binds to the predicted CDX elements in this region of the KRT20 promoter in vivo. In addition, immunohistochemistry showed expression of CDX1 parallels that of KRT20 in the normal crypt, which further supports their close relationship. In summary, our observations strongly imply that KRT20 is directly regulated by CDX1, and therefore suggest a role for CDX1 in maintaining differentiation in intestinal epithelial cells. Because a key feature of the development of a cancer is an unbalanced program of proliferation and differentiation, dysregulation of CDX1 may be an advantage for the development of a colorectal carcinoma. This could, therefore, explain the relatively frequent down regulation of CDX1 in colorectal carcinomas by hypermethylation.
机译：CDX1是在肠道发育和分化中起关键作用的转录因子。但是，CDX1的下游靶标与其紧密同源物CDX2的下游靶标的定义较差。我们在这里报告使用微阵列基因表达分析和其他方法鉴定CDX1的下游目标。角蛋白20（KRT20）是中间细丝的成员，也是肠道分化的著名标记，最初被鉴定为可能由CDX1直接调控的基因之一。在一组38个结直肠癌细胞系中，CDX1和KRT20 mRNA表达显着相关。 KRT20启动子的缺失和突变分析表明，用于CDX1控制KRT20表达的最小调节区在KRT20转录起始位点上游246 bp之内。 ChIP分析证实CDX1在体内与KRT20启动子这一区域的预测CDX元素结合。此外，免疫组化显示正常隐窝中CDX1的表达与KRT20相似，这进一步支持了它们的密切关系。总而言之，我们的观察结果强烈暗示KRT20受CDX1直接调节，因此暗示CDX1在维持肠上皮细胞分化中的作用。因为癌症发展的关键特征是增殖和分化的程序不平衡，所以CDX1的失调可能是结直肠癌发展的优势。因此，这可以解释高甲基化在大肠癌中CDX1相对频繁的下调。

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    Carol W. M. Chan; Newton A. Wong; Ying Liu; David Bicknell; Helen Turley; Laura Hollins; Crispin J. Miller; Jennifer L. Wilding; Walter F. Bodmer;

  • 作者单位

    Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, OX3 9DS, United Kingdom;

    Department of Histopathology, Bristol Royal Infirmary, Marlborough Street, Bristol BS2 8HW, United Kingdom;

    Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, OX3 9DS, United Kingdom;

    Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, OX3 9DS, United Kingdom;

    Cancer Research UK Tumour Pathology Group, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, 0X3 9DU, United Kingdom;

    Applied Computational Biology and Bioinformatics Group, The Paterson Institute For Cancer Research, University of Manchester, Christie Hospital Site, Wilmslow Road, Manchester M20 4BX, United Kingdom;

    Applied Computational Biology and Bioinformatics Group, The Paterson Institute For Cancer Research, University of Manchester, Christie Hospital Site, Wilmslow Road, Manchester M20 4BX, United Kingdom;

    Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, OX3 9DS, United Kingdom;

    Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, OX3 9DS, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    colorectal cancer; epithelial; cell lines; methylation; cancer stem cells;

    机译：大肠癌;上皮;细胞系;甲基化;癌干细胞;

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