Matrix Metalloproteinase 1 promotes tumor formation and lung metastasis in an intratibial injection osteosarcoma mouse model
Matrix Metalloproteinase 1 promotes tumor formation and lung metastasis in an intratibial injection osteosarcoma mouse model
复制标题
DOI：
10.1016/j.bbadis.2012.11.006
复制
发表时间：
2013-02-01
影响因子：
6.2
通讯作者：
Fuchs, Bruno
中科院分区：
文献类型：
--
作者：
Husmann, Knut;Arlt, Matthias J. E.;Fuchs, Bruno
细胞外基质（ECM）的蛋白水解降解是肿瘤侵袭过程中的一个重要过程。基质金属蛋白酶1（MMP-1）是降解骨ECM的主要成分I型胶原的蛋白酶之一。在本研究中，MMP-1在骨肉瘤（OS）肿瘤的生长和转移的生物学相关性进行了研究，在体外和体内。原代培养的人OS细胞表达MMP-1编码mRNA的水平明显高于正常人骨细胞。此外，MMP-1 mRNA和蛋白在高转移性人骨肉瘤143-B细胞系中的表达显著高于非转移性亲本HOS细胞系。在143-B细胞中，稳定的shRNA介导的MMP-1下调损害了与I型胶原的粘附和锚定非依赖性生长，反映在软琼脂中生长能力降低。胫骨内注射SOD小鼠后，MMP-1表达下调的143-B细胞形成的原发性肿瘤较小，肺微转移和大转移的数量显著低于对照细胞。相反，HOS细胞稳定过表达MMP-1表现出增强的粘附能力，胶原蛋白I和加速锚定非依赖性生长相比，空载体转导的对照细胞。此外，最重要的是，个别MMP-1过度表达的HOS细胞能够形成溶骨性原发性肿瘤和肺转移，而HOS对照细胞没有发展任何肿瘤或转移后，胫骨内注射。本研究的结果揭示了MMP-1在OS原发肿瘤和肺转移形成中的重要作用，肺是OS转移的主要器官。(C)2012爱思唯尔有限公司版权所有。
Proteolytic degradation of the extracellular matrix (ECM) is an important process during tumor invasion. Matrix Metalloproteinase 1 (MMP-1) is one of the proteases that degrade collagen type I, a major component of bone ECM. In the present study, the biological relevance of MMP-1 in osteosarcoma (OS) tumor growth and metastasis was investigated in vitro and in vivo. Human OS cells in primary culture expressed MMP-1 encoding mRNA at considerably higher levels than normal human bone cells. In addition, MMP-1 mRNA and protein expression in the highly metastatic human osteosarcoma 143-B cell line was remarkably higher than in the non-metastatic parental HOS cell line. Stable shRNA-mediated downregulation of MMP-1 in 143-B cells impaired adhesion to collagen I and anchorage-independent growth, reflected by a reduced ability to grow in soft agar. Upon intratibial injection into SOD mice, 143-B cells with shRNA-downregulated MMP-1 expression formed smaller primary tumors and significantly lower numbers of lung micro- and macrometastases than control cells. Conversely, HOS cells stably overexpressing MMP-1 showed an enhanced adhesion capability to collagen I and accelerated anchorage-independent growth compared to empty vector-transduced control cells. Furthermore, and most importantly, individual MMP-1 overexpression in HOS cells enabled the formation of osteolytic primary tumors and lung metastasis while the HOS control cells did not develop any tumors or metastases after intratibial injection. The findings of the present study reveal an important role of MMP-1 in OS primary tumor and metastasis formation to the lung, the major organ of OS metastasis. (C) 2012 Elsevier B.V. All rights reserved.