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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions
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A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions

机译：染色体缺失中的一组协同合作的抑癌基因候选物

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摘要

The large chromosomal deletions frequently observed in cancer genomes are often thought to arise as a "two-hit" mechanism in the process of tumor-suppressor gene (TSG) inactivation. Usingamurine model system of hepatocellular carcinoma (HCC) and in vivo RNAi, we test an alternative hypothesis, that such deletions can arise from selective pressure to attenuate the activity of multiple genes. By targeting the mouse orthologs of genes frequently deleted on human 8p22 and adjacent regions, which are lost in approximately half of several other major epithelial cancers, we provide evidence suggesting that multiple genes on chromosome 8p can cooperatively inhibit tumorigenesis in mice, and that their cosuppression can synergistically promote tumor growth. In addition, in human HCC patients, the combined down-regulation of functionally validated 8p TSGs is associated with poor survival, in contrast to the down-regulation of any individual gene. Our data imply that large cancer-associated deletions can produce phenotypes distinct from those arising through loss of a single TSG, and as such should be considered and studied as distinct mutational events.
机译：在癌症基因组中经常观察到的大染色体缺失通常被认为是肿瘤抑制基因（TSG）失活过程中的“两次打击”机制。使用肝细胞癌（HCC）和体内RNAi的动物模型系统，我们测试了另一种假设，即这种缺失可能来自选择性压力，从而减弱了多个基因的活性。通过针对人类8p22及其附近区域经常缺失的基因的小鼠直系同源基因，这些基因在大约几种其他主要上皮癌中丢失，我们提供了证据表明8p染色体上的多个基因可以协同抑制小鼠的肿瘤发生，以及它们的共抑制可以协同促进肿瘤的生长。此外，与任何单个基因的下调相反，在人类HCC患者中，经功能验证的8p TSG的联合下调与不良的生存率相关。我们的数据表明，与癌症相关的大型缺失可产生与单个TSG缺失引起的表型不同的表型，因此，应将其视为独特的突变事件进行研究。

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  • 作者

    Wen Xue; Thomas Kitzing; Stephanie Roessler; Johannes Zuber; Alexander Krasnitz; Nikolaus Schultz; Kate Revill; Susann Weissmueller; Amy R. Rappaport; Janelle Simon; Jack Zhang; Weijun Luo; James Hicks; Lars Zender; Xin Wei Wang; Scott Powers; Michael Wigler; Scott W. Lowe;

  • 作者单位

    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139;

    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, Department of Cancer Biology and Genetics, Sloan-Kettering Institute,New York, NY 10065;

    Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;

    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;

    Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;

    Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, Department of Cancer Biology and Genetics, Sloan-Kettering Institute,New York, NY 10065;

    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;

    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center,New York, NY 10065 Department of Cancer Biology and Genetics, Sloan-Kettering Institute,New York, NY 10065;

    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;

    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;

    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;

    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724,Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany and Department of Gastroenterology and Hepatology, University of Hannover Medical School, 30625 Hannover, Germany;

    Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;

    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;

    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724;

    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center,New York, NY 10065 Department of Cancer Biology and Genetics, Sloan-Kettering Institute,New York, NY 10065;

  • 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

    cancer genomics; chromosome 8p deletion; RNAi screen;

    机译：癌症基因组学染色体8p缺失;RNAi筛选;

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