Overexpression of collagenase 1 (MMP-1) is mediated by the ERK pathway in invasive melanoma cells -: Role of BRAF mutation and fibroblast growth factor signaling
Overexpression of collagenase 1 (MMP-1) is mediated by the ERK pathway in invasive melanoma cells -: Role of BRAF mutation and fibroblast growth factor signaling
复制标题
侵袭性黑色素瘤细胞中胶原酶1（MMP-1）的过表达是由ERK通路介导的--： BRAF 突变和成纤维细胞生长因子信号的作用
DOI：
10.1074/jbc.m405102200
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发表时间：
2004-08-06
影响因子：
4.8
通讯作者：
Brinckerhoff, CE
中科院分区：
文献类型：
--
作者：
Huntington, JT;Shields, JM;Brinckerhoff, CE
黑色素瘤的进展是一个多步骤的过程，其中病变的厚度和肿瘤浸润的深度是临床结果的最佳预后指标。细胞外基质中的间质胶原的降解是肿瘤侵袭和转移的组成部分，并且这种降解的大部分由基质金属蛋白酶（MMP）家族的成员胶原酶-1（MMP-1）介导。MMP-1水平在黑色素瘤进展期间增加，其中它们与较短的无病生存期相关。Ras/Raf/ MEK/ERK丝裂原活化蛋白激酶（MAPK）通路是黑色素瘤细胞增殖的主要调节因子。最近，BRAF已被确定为激活突变的常见位点，尽管许多报道关注其促生长作用，但该途径也与转移性疾病的进展有关。在这项研究中，我们描述了四个黑色素瘤细胞株，产生高水平的MMP-1组成。在每种细胞系中，Ras/Raf/ MEK/ERK途径是组成型活性的，并且是驱动MMP-1产生的主导途径。该途径的激活是由于BRAF（三种细胞系）或自分泌成纤维细胞生长因子信号传导（一种细胞系）中的激活突变而引起的。此外，阻断MEK/ ERK活性可抑制黑素瘤细胞增殖并消除胶原降解，从而降低其转移潜力。重要的是，这种对侵入行为的抑制可以在细胞增殖和存活没有任何可检测到的变化的情况下发生。因此，这种MAPK通路的组成性激活不仅促进黑素瘤细胞增殖的增加，而且对于获得侵袭性表型也是重要的。
Melanoma progresses as a multistep process where the thickness of the lesion and depth of tumor invasion are the best prognostic indicators of clinical outcome. Degradation of the interstitial collagens in the extracellular matrix is an integral component of tumor invasion and metastasis, and much of this degradation is mediated by collagenase-1 (MMP-1), a member of the matrix metalloproteinase (MMP) family. MMP-1 levels increase during melanoma progression where they are associated with shorter disease-free survival. The Ras/Raf/ MEK/ERK mitogen-activated protein kinase ( MAPK) pathway is a major regulator of melanoma cell proliferation. Recently, BRAF has been identified as a common site of activating mutations, and, although many reports focus on its growth-promoting effects, this pathway has also been implicated in progression toward metastatic disease. In this study, we describe four melanoma cell lines that produce high levels of MMP-1 constitutively. In each cell line the Ras/Raf/ MEK/ERK pathway is constitutively active and is the dominant pathway driving the production of MMP-1. Activation of this pathway arises due to either an activating mutation in BRAF ( three cell lines) or autocrine fibroblast growth factor signaling ( one cell line). Furthermore, blocking MEK/ ERK activity inhibits melanoma cell proliferation and abrogates collagen degradation, thus decreasing their metastatic potential. Importantly, this inhibition of invasive behavior can occur in the absence of any detectable changes in cell proliferation and survival. Thus, constitutive activation of this MAPK pathway not only promotes the increased proliferation of melanoma cells but is also important for the acquisition of an invasive phenotype.