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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1
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Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1

机译：Snail1诱导癌细胞中MT1-MMP和依赖MT2-MMP的基底膜迁移程序

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摘要

The ability of carcinoma cells arising at primary sites to cross their underlying basement membrane (BM), a specialized form of extracellular matrix that subtends all epithelial cells, and to access the host vasculature are central features of the malignant phenotype. The initiation of the invasive phenotype has been linked to the aberrant expression of zinc-finger transcriptional repressors, like SnaiM, which act by triggering an epithelial-mesenchymal cell-like transformation (EMT-like) via the regulation of largely undefined, downstream effectors. Herein, we find that SnaiM induces cancer cells to (i) degrade and perforate BM barriers, (ii) initiate angiogenesis, and (iii) and intravasate vascular networks in vivo via a matrix metalloproteinase (MMP)-dependent process. Unexpectedly, the complete SnaiM invasion program can be recapitulated by expressing directly either of the membrane-anchored metalloproteinases, MT1-MMP or MT2-MMP. The pro-invasive, angiogenic, and metastatic activities of MT1-MMP and MT2-MMP are unique relative to all other metalloproteinase family members and cannot be mimicked in vivo by the secreted MMPs, MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, or MMP-13. Further, siRNA-specific silencing of MT1-MMP and MT2-MMP ablates completely the ability of SnaiM to drive cancer cell BM invasion, induce angiogenesis, or trigger intravasation. Taken together, these data demonstrate that MT1-MMP and MT2-MMP cooperatively function as direct-acting, pro-invasive factors that confer Snail1-triggered cells with the key activities most frequently linked to morbidity and mortality in cancer.
机译：在主要部位产生的癌细胞穿过其基础基底膜（BM）的能力是恶性表型的主要特征，该基底膜是对付所有上皮细胞的细胞外基质的一种特殊形式，可以进入宿主的脉管系统。侵袭性表型的启动与锌指转录阻遏物（如SnaiM）的异常表达有关，后者通过调节很大程度上不确定的下游效应子，触发上皮间质细胞样转化（EMT样）而发挥作用。在本文中，我们发现SnaiM诱导癌细胞通过基质金属蛋白酶（MMP）依赖性过程在体内降解（i）降解并穿透BM屏障，（ii）启动血管生成，以及（iii）和血管内血管网络。出乎意料的是，可以通过直接表达膜锚定的金属蛋白酶MT1-MMP或MT2-MMP来概括完整的SnaiM入侵程序。相对于所有其他金属蛋白酶家族成员，MT1-MMP和MT2-MMP的侵袭性，血管生成和转移活性是独特的，并且在体内不能被分泌的MMP，MMP-1，MMP-2，MMP-3模仿， MMP-7，MMP-9或MMP-13。此外，MT1-MMP和MT2-MMP的siRNA特异性沉默可完全消除SnaiM驱动癌细胞BM侵袭，诱导血管生成或触发血管内插入的能力。综上所述，这些数据表明MT1-MMP和MT2-MMP协同作用为直接作用的促侵袭因子，使Snail1触发的细胞具有最常与癌症发病率和死亡率相关的关键活性。

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  • 作者

    Ichiro Ota; Xiao-Yan Li; Yuexian Hu; Stephen J. Weiss;

  • 作者单位

    Division of Molecular Medicine and Genetics, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, Ml 48109 Department of Otolaryngology, Nara Medical University, Nara 634-8522, Japan;

    Division of Molecular Medicine and Genetics, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, Ml 48109;

    Division of Molecular Medicine and Genetics, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, Ml 48109;

    Division of Molecular Medicine and Genetics, Department of Internal Medicine, Life Sciences Institute, University of Michigan, Ann Arbor, Ml 48109;

  • 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

    EMT; extracellular matrix; snail;

    机译：EMT;细胞外基质蜗牛;

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