Matrix Metalloproteinase Mmp-1a Is Dispensable for Normal Growth and Fertility in Mice and Promotes Lung Cancer Progression by Modulating Inflammatory Responses
Matrix Metalloproteinase Mmp-1a Is Dispensable for Normal Growth and Fertility in Mice and Promotes Lung Cancer Progression by Modulating Inflammatory Responses
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DOI：
10.1074/jbc.m112.439893
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发表时间：
2013-05-17
影响因子：
4.8
通讯作者：
Lopez-Otin, Carlos
中科院分区：
文献类型：
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作者：
Fanjul-Fernandez, Miriam;Folgueras, Alicia R.;Lopez-Otin, Carlos
人基质金属蛋白酶-1是一种与包括癌症在内的许多病理疾病反复相关的基质金属蛋白酶。因此，在包括结直肠癌、乳腺癌和肺癌在内的多种晚期癌症中，MMP1的过度表达是一个预后不良的标志物。此外，基质金属蛋白酶-1在黑色素瘤、乳腺和前列腺癌细胞的转移行为中起关键作用。然而，由于缺乏体内模型，对基质金属蛋白酶-1在癌症中的相关性的功能和机制研究一直受到阻碍。在这项工作中，我们产生了缺乏Mmp1a的小鼠，Mmp1a是人类MMP1的同源基因。Mmp1a(-/-)小鼠存活和生育能力强，没有表现出明显的异常，这有助于癌症易感性的研究。这些研究表明，在Mmp1a(-/-)小鼠中，化学致癌物诱发肺癌的易感性降低。组织病理学分析表明，Mmp1a(-/-)小鼠产生的肿瘤比野生型小，这与缺乏基质金属蛋白酶-1a阻碍肿瘤进展的观点一致。蛋白质组学分析显示，与野生型相比，Mmp1a(-/-)小鼠肺组织中几丁质酶-3样蛋白的水平降低，晚期糖基化终产物受体及其配体S100A8的积聚。这些发现表明，基质金属蛋白酶-1a可能通过调节Th1/Th2对化学致癌物的炎症反应的极化而在肿瘤进展中发挥作用。在这些结果的基础上，我们认为Mmp1a基因敲除小鼠为在生理和病理条件下分析人基质金属蛋白酶-1的功能提供了一个很好的体内模型。
Human MMP-1 is a matrix metalloproteinase repeatedly associated with many pathological conditions, including cancer. Thus, MMP1 overexpression is a poor prognosis marker in a variety of advanced cancers, including colorectal, breast, and lung carcinomas. Moreover, MMP-1 plays a key role in the metastatic behavior of melanoma, breast, and prostate cancer cells. However, functional and mechanistic studies on the relevance of MMP-1 in cancer have been hampered by the absence of an in vivo model. In this work, we have generated mice deficient in Mmp1a, the murine ortholog of human MMP1. Mmp1a(-/-) mice are viable and fertile and do not exhibit obvious abnormalities, which has facilitated studies of cancer susceptibility. These studies have shown a decreased susceptibility to develop lung carcinomas induced by chemical carcinogens in Mmp1a(-/-) mice. Histopathological analysis indicated that tumors generated in Mmp1a(-/-) mice are smaller than those of wild-type mice, consistently with the idea that the absence of Mmp-1a hampers tumor progression. Proteomic analysis revealed decreased levels of chitinase-3-like 3 and accumulation of the receptor for advanced glycation end-products and its ligand S100A8 in lung samples from Mmp1a(-/-) mice compared with those from wild-type. These findings suggest that Mmp-1a could play a role in tumor progression by modulating the polarization of a Th1/Th2 inflammatory response to chemical carcinogens. On the basis of these results, we propose that Mmp1a knock-out mice provide an excellent in vivo model for the functional analysis of human MMP-1 in both physiological and pathological conditions.