Overexpression of tissue inhibitors of metalloproteinase 2 up-regulates NF-kappaB activity in melanoma cells.
Overexpression of tissue inhibitors of metalloproteinase 2 up-regulates NF-kappaB activity in melanoma cells.
复制标题
金属蛋白酶 2 组织抑制剂的过度表达上调黑色素瘤细胞中的 NF-κB 活性。
DOI：
10.1186/1750-2187-4-4
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发表时间：
2009-07-23
影响因子：
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通讯作者：
Stetler-Stevenson WG
中科院分区：
文献类型：
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作者：
Sun J;Stetler-Stevenson WG
基质金属蛋白酶在细胞外基质的重塑中发挥作用，而细胞外基质在许多正常和病理过程中是不可或缺的，如形态发生、血管生成、组织修复和肿瘤侵袭。金属蛋白酶家族的组织抑制因子包括金属蛋白酶组织抑制因子-2(TIMP-2)，调节多功能金属蛋白酶的活性。已知，在黑色素瘤细胞中，作为NF-κB途径靶基因的IL-8表达增加。然而，TIMP-2的表达是否调节了NF-κB通路尚不清楚。在本研究中，我们使用稳定的黑色素瘤细胞系A2058、高表达TIMP-2的A2058T2-1和低表达TIMP-2的A2058T2R-7，以确定TIMP-2对NF-κB活性的调节。我们发现，在过表达TIMP-2的A2058T2-1中，IL-8的分泌和IL-8mRNA的表达显著增加。与亲代A2058细胞相比，高表达TIMP-2的细胞具有较低的基础水平的I-κBα(核因子-κB的抑制物)。TIMP-2过表达可提高转录水平的NF-κB活性。相反，低表达TIMP-2的A2058T2R-7具有与亲本A2058细胞相似的NF-κB活性。与亲本A2058细胞相比，TIMP-2过表达细胞中肿瘤坏死因子诱导的细胞凋亡明显减少。TIMP-2过表达对细胞有保护作用。我们的研究结果表明，TIMP-2蛋白的表达水平可以直接调节人黑色素瘤细胞中的NF-κB通路。
Matrix Metalloproteinase functions in the remodeling of the extracellular matrix that is integral for many normal and pathological processes such as morphogenesis, angiogenesis, tissue repair, and tumor invasion. The tissue inhibitor of the metalloproteinase family including the tissue inhibitor of metalloproteinase-2 (TIMP-2) regulates the activity of multifunctional metalloproteinase. It is known that IL-8, the target gene of NF-κB pathway, increases in the melanoma cells. However, it is not clear whether the TIMP-2 expression regulates the NF-κB pathway. In this study, we have used stable melanoma cell lines, parental A2058, A2058T2-1 overexpressing TIMP-2, and A2058T2R-7 underexpressing TIMP-2, to determine the TIMP-2 regulation of the NF-κB activity. We found that the IL-8 secretion and IL-8 mRNA expression significantly increased in the A2058T2-1 overexpressing TIMP-2. TIMP-2 overexpressed cells had the lower basal level of IκBα, the inhibitor of NF-κB, compared to the parental A2058 cells. The transcriptional NF-κB activity was increased by the TIMP-2 overexpression. In contrast, A2058T2R-7 underexpressing TIMP-2 had the similar NF-κB activity as that in the parental A2058 cell. The apoptotic cells induced by TNF were less in TIMP-2 over-expression cells compared to those in the parental A2058 cells. TIMP-2 over-expression was able to protect cells from apoptosis. Our data demonstrate that the expression level of TIMP-2 protein can directly modulate the NF-κB pathway in human melanoma cells.