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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer
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Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer

机译：Jagged1是结直肠癌中Wnt和Notch通路之间的病理联系

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摘要

Notch has been linked to β-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/β-catenin (down-regulated when blocking Wnt/β-catenin) that are directly regulated by Notch (repressed by y-secretase inhibitors and up-regulated by active Notch 1 in the absence of β-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through β-catenin-mediated transcrip-tional activation of the Notch-ligand Jagged 1. Consistently, expression of activated Notch1 partially reverts the effects of blocking Wnt/β-catenin pathway in tumors implanted s.c. in nude mice. Crossing APC~(Min/+) with Jagged1~(+/△) mice is sufficient to significantly reduce the size of the polyps arising in the APC mutant background indicating that Notch is an essential modulator of tumorigenesis induced by nuclear β-catenin. We show that this mechanism is operating in human tumors from Familial Adenomatous Polyposis patients. We conclude that Notch activation, accomplished by β-catenin-mediated up-regulation of Jagged 1, is required for tumorigenesis in the intestine. The Notch-specific genetic signature is sufficient to block differentiation and promote vasculogenesis in tumors whereas proliferation depends on both pathways.
机译：Notch与β-catenin依赖的肿瘤发生有关。然而，尚不清楚导致Notch活化的机制和Notch途径对结直肠癌的贡献。通过微阵列分析，我们鉴定了一组由Notch直接调节的Wnt /β-catenin下游基因（阻断Wnt /β-catenin时被下调），这些基因直接受Notch调节（受y-分泌酶抑制剂抑制，而由活跃Notch上调1（在没有β-catenin信号传导的情况下）。我们证明Notch通过β-catenin介导的Notch-ligand Jagged 1转录激活在结直肠癌细胞中位于Wnt的下游。一致地，Notch1的表达部分地逆转了肿瘤中阻断Wnt /β-catenin通路的作用。植入sc在裸鼠中。将APC_（Min / +）与Jagged1〜（+ /△）小鼠杂交足以显着减小APC突变体背景中出现的息肉大小，这表明Notch是由核β-catenin诱导的肿瘤发生的重要调节剂。我们显示该机制在家族性腺瘤性息肉病患者的人类肿瘤中起作用。我们得出的结论是，Notch激活是由β-catenin介导的锯齿状1的上调完成的，是肠道肿瘤发生所必需的。 Notch特异的遗传特征足以阻止肿瘤的分化并促进血管生成，而增殖取决于这两种途径。

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  • 作者

    Veronica Rodilla; Alberto Villanueva; Antonia Obrador-Hevia; Alex Robert-Moreno; Vanessa Fernandez-Majada; Andrea Grilli; Nuria Lopez-Bigas; Nicolas Bellora; M. Mar Alba; Ferran Torres; Mireia Dunach; Xavier Sanjuan; Sara Gonzalez; Thomas Gridley; Gabriel Capella; Anna Bigas; Lluis Espinosa;

  • 作者单位

    Institut d'lnvestigacio Biomedica de Bellvitge Gran Via km 2.7, Hospitalet and Institut Municipal d'lnvestigacions Mediques-Hospital del Mar, Dr. Aiguader 88, 08003 Barcelona, Spain;

    Institut d'lnvestigacio Biomedica de Bellvitge-Institut Catala d'Oncologia Gran Via km 2.7, Hospitalet, 08907 Barcelona, Spain;

    Institut d'lnvestigacio Biomedica de Bellvitge-Institut Catala d'Oncologia Gran Via km 2.7, Hospitalet, 08907 Barcelona, Spain;

    Institut d'lnvestigacio Biomedica de Bellvitge Gran Via km 2.7, Hospitalet and Institut Municipal d'lnvestigacions Mediques-Hospital del Mar, Dr. Aiguader 88, 08003 Barcelona, Spain;

    Institut d'lnvestigacio Biomedica de Bellvitge Gran Via km 2.7, Hospitalet and Institut Municipal d'lnvestigacions Mediques-Hospital del Mar, Dr. Aiguader 88, 08003 Barcelona, Spain;

    Tundacio Institut Municipal de Investigacio Medica, Universitat Pompeu Fabra, Institucio Catalana de Recerca I Estudis Avanc.ats, Barcelona, Spain;

    Tundacio Institut Municipal de Investigacio Medica, Universitat Pompeu Fabra, Institucio Catalana de Recerca I Estudis Avanc.ats, Barcelona, Spain;

    Tundacio Institut Municipal de Investigacio Medica, Universitat Pompeu Fabra, Institucio Catalana de Recerca I Estudis Avanc.ats, Barcelona, Spain;

    Tundacio Institut Municipal de Investigacio Medica, Universitat Pompeu Fabra, Institucio Catalana de Recerca I Estudis Avanc.ats, Barcelona, Spain;

    Laboratory of Biostatistics and Epidemiology, Universitat Autonoma de Barcelona, Statistics and Methodology Support Unit, Institut d'lnvestigacions Biomediques August Pi I Sunyer, Hospital Clinic, 08036 Barcelona, Spain;

    Centre d'Estudis Bioffsica I Departmento Bioquimica I Biologia Molecular, Facultat de Medicina, Universitat Autonoma de Barcelona, 08193 Barcelona, Spain;

    Servei Anatomia Patologica, Hospital Universitari de Bellvitge, Feixa Llarga, Hospitalet, 08907 Barcelona, Spain;

    Institut d'lnvestigacio Biomedica de Bellvitge-Institut Catala d'Oncologia Gran Via km 2.7, Hospitalet, 08907 Barcelona, Spain;

    The Jackson Laboratory, Bar Harbor, MA 04609;

    Institut d'lnvestigacio Biomedica de Bellvitge-Institut Catala d'Oncologia Gran Via km 2.7, Hospitalet, 08907 Barcelona, Spain;

    Institut d'lnvestigacio Biomedica de Bellvitge Gran Via km 2.7, Hospitalet and Institut Municipal d'lnvestigacions Mediques-Hospital del Mar, Dr. Aiguader 88, 08003 Barcelona, Spain;

    Institut d'lnvestigacio Biomedica de Bellvitge Gran Via km 2.7, Hospitalet and Institut Municipal d'lnvestigacions Mediques-Hospital del Mar, Dr. Aiguader 88, 08003 Barcelona, Spain;

  • 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

    beta-catenin; APC; intestine; crosstalk;

    机译：β-catenin;APC;肠;相声;

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