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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in Apc~(Min/+) mice with natural ligands
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Aryl hydrocarbon receptor suppresses intestinal carcinogenesis in Apc~(Min/+) mice with natural ligands

机译：芳烃受体抑制具有天然配体的Apc〜（Min / +）小鼠肠道癌变

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摘要

Intestinal cancer is one of the most common human cancers. Aberrant activation of the canonical Wnt signaling cascade, for example, caused by adenomatous polyposis coli (APC) gene mutations, leads to increased stabilization and accumulation of β-catenin, resulting in initiation of intestinal carcinogenesis. The aryl hydrocarbon receptor (AhR) has dual roles in regulating intracellular protein levels both as a ligand-activated transcription factor and as a ligand-dependent E3 ubiquitin ligase. Here, we show that the AhR E3 ubiquitin ligase has a role in suppression of intestinal carcinogenesis by a previously undescribed ligand-dependent β-catenin degradation pathway that is independent of and parallel to the APC system. This function of AhR is activated by both xenobiotics and natural AhR ligands, such as indole derivatives that are converted from dietary tryptophan and glucosino-lates by intestinal microbes, and suppresses intestinal tumor development in Apc~(Min/+) mice. These findings suggest that che-moprevention with naturally-occurring and chemically-designed AhR ligands can be used to successfully prevent intestinal cancers.
机译：肠癌是最常见的人类癌症之一。例如，由腺瘤性息肉病大肠杆菌（APC）基因突变引起的规范Wnt信号级联反应的异常激活，会导致β-catenin的稳定性和积累增加，从而引发肠道致癌作用。芳烃受体（AhR）在调节细胞内蛋白水平方面既起配体激活的转录因子作用，又起配体依赖性E3泛素连接酶的作用。在这里，我们显示，AhR E3泛素连接酶通过先前未描述的依赖于配体的β-catenin降解途径（独立于APC系统并与之平行）而在抑制肠癌发生中起作用。外源生物和天然AhR配体均可激活AhR的这种功能，例如吲哚衍生物可通过肠道微生物从饮食色氨酸和葡萄糖苷转化而来，并抑制Apc〜（Min / +）小鼠的肠道肿瘤发展。这些发现表明，用天然存在的和化学设计的AhR配体进行化学预防可以成功地预防肠道癌。

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  • 作者

    Kaname Kawajiri; Yasuhito Kobayashi; Fumiaki Ohtake; Togo lkuta; Yoshibumi Matsushima; Junsei Mimura; Sven Pettersson; Richard S. Pollenz; Toshiyuki Sakaki; Takatsugu Hirokawa; Tetsu Akiyama; Masafumi Kurosumi; Lorenz Poellinger; Shigeaki Kato; Yoshiaki Fujii-Kuriyama;

  • 作者单位

    Research Institute for Clinical Oncology, 818 Komuro, Ina, Saitama, 362-0806, Japan;

    Hospital, Saitama Cancer Center, 818 Komuro, Ina, Saitama, 362-0806, Japan;

    Exploratory Research for Advanced Technology and Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan;

    Research Institute for Clinical Oncology, 818 Komuro, Ina, Saitama, 362-0806, Japan;

    Research Institute for Clinical Oncology, 818 Komuro, Ina, Saitama, 362-0806, Japan;

    Tsukuba Advanced Research Alliance Center, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, 305-8577, Japan;

    Germ-Free Facility and Molecular Biology, Karolinska Institute, S-171 77 Stockholm, Sweden;

    Department of Biology, University of South Florida, Tampa, FL 33620;

    Department of Biotechnology, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama, 939-0398, Japan;

    Computational Biology Research Center, National Institute of Advanced Industrial Science and Technology, 2-42 Aomi, Koto-ku, Tokyo, 135-0064, Japan;

    Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan;

    Hospital, Saitama Cancer Center, 818 Komuro, Ina, Saitama, 362-0806, Japan;

    Department of Cell and Molecular Biology, Karolinska Institute, S-171 77 Stockholm, Sweden;

    Exploratory Research for Advanced Technology and Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan;

    Exploratory Research for Advanced Technology and Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan Tsukuba Advanced Research Alliance Center, University of Tsukuba, Tennodai, Tsukuba, Ibaraki, 305-8577, Japan;

  • 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
  • 中图分类
  • 关键词

    cecal cancer; ubiquitin ligase; β-catenin; tumor chemoprevention;

    机译：盲肠癌;泛素连接酶β-连环蛋白;肿瘤化学预防;

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