Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability
Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability
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DOI：
10.1038/nature03688
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发表时间：
2005-07-07
期刊：
影响因子：
64.8
通讯作者：
Bissell, MJ
中科院分区：
文献类型：
--
作者：
Radisky, DC;Levy, DD;Bissell, MJ
肿瘤微环境可能是一种强大的致癌物，不仅通过促进癌症的进展和激活休眠的癌细胞，而且通过刺激肿瘤的形成(1)。我们已经研究了基质分解素-1/基质金属蛋白酶-3(MMP3)，这是一种在许多乳腺肿瘤中上调的间质酶(2)，并发现MMP3可以在培养细胞中引起上皮-间充质转化(EMT)和恶性转化(3-5)，以及在转基因小鼠中引起基因组不稳定的乳腺癌(3)。在这里，我们解释了基质金属蛋白酶-3发挥这些作用的分子途径：小鼠乳腺上皮细胞暴露于基质金属蛋白酶-3诱导一种选择性剪接形式的rac1的表达，从而导致细胞内活性氧物种(ROS)的增加。ROS刺激转录因子Snail和EMT的表达，导致DNA氧化损伤和基因组不稳定。这些发现确定了一种以前未描述的途径，即乳腺肿瘤微环境的一个组成部分改变培养中的细胞结构和体内的组织结构，导致恶性转化。
The tumour microenvironment can be a potent carcinogen, not only by facilitating cancer progression and activating dormant cancer cells, but also by stimulating tumour formation(1). We have previously investigated stromelysin-1/matrix metalloproteinase-3 (MMP-3), a stromal enzyme upregulated in many breast tumours(2), and found that MMP-3 can cause epithelial-mesenchymal transition (EMT) and malignant transformation in cultured cells(3-5), and genomically unstable mammary carcinomas in transgenic mice(3). Here we explain the molecular pathways by which MMP-3 exerts these effects: exposure of mouse mammary epithelial cells to MMP-3 induces the expression of an alternatively spliced form of Rac1, which causes an increase in cellular reactive oxygen species (ROS). The ROS stimulate the expression of the transcription factor Snail and EMT, and cause oxidative damage to DNA and genomic instability. These findings identify a previously undescribed pathway in which a component of the breast tumour microenvironment alters cellular structure in culture and tissue structure in vivo, leading to malignant transformation.