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金属蛋白酶组织抑制剂2的过表达上调黑色素瘤细胞中的核因子κB活性。

Overexpression of tissue inhibitors of metalloproteinase 2 up-regulates NF-kappaB activity in melanoma cells.

作者信息

Sun Jun, Stetler-Stevenson William G

机构信息

Department of Medicine, Department of Microbiology and Immunology, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA.

出版信息

J Mol Signal. 2009 Jul 23;4:4. doi: 10.1186/1750-2187-4-4.

DOI:10.1186/1750-2187-4-4
PMID:19627587
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2720935/
Abstract

BACKGROUND

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-kappaB pathway, increases in the melanoma cells. However, it is not clear whether the TIMP-2 expression regulates the NF-kappaB 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-kappaB activity.

RESULTS

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 IkappaBalpha, the inhibitor of NF-kappaB, compared to the parental A2058 cells. The transcriptional NF-kappaB activity was increased by the TIMP-2 overexpression. In contrast, A2058T2R-7 underexpressing TIMP-2 had the similar NF-kappaB 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.

CONCLUSION

Our data demonstrate that the expression level of TIMP-2 protein can directly modulate the NF-kappaB pathway in human melanoma cells.

摘要

背景

基质金属蛋白酶在细胞外基质重塑中发挥作用，而细胞外基质重塑对于许多正常和病理过程（如形态发生、血管生成、组织修复和肿瘤侵袭）不可或缺。金属蛋白酶组织抑制因子家族，包括金属蛋白酶组织抑制因子-2（TIMP-2），可调节多功能金属蛋白酶的活性。已知作为核因子κB（NF-κB）通路靶基因的白细胞介素-8（IL-8）在黑色素瘤细胞中表达增加。然而，尚不清楚TIMP-2表达是否调节NF-κB通路。在本研究中，我们使用了稳定的黑色素瘤细胞系，亲本A2058、过表达TIMP-2的A2058T2-1以及低表达TIMP-2的A2058T2R-7，以确定TIMP-2对NF-κB活性的调节作用。

结果

我们发现，过表达TIMP-2的A2058T2-1中IL-8分泌和IL-8 mRNA表达显著增加。与亲本A2058细胞相比，过表达TIMP-2的细胞中NF-κB抑制剂IκBα的基础水平较低。TIMP-2过表达使转录性NF-κB活性增加。相反，低表达TIMP-2的A2058T2R-7的NF-κB活性与亲本A2058细胞相似。与亲本A2058细胞相比，TIMP-2过表达细胞中由肿瘤坏死因子（TNF）诱导的凋亡细胞较少。TIMP-2过表达能够保护细胞免于凋亡。

结论

我们的数据表明，TIMP-2蛋白的表达水平可直接调节人黑色素瘤细胞中的NF-κB通路。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7080/2720935/9dd1b4aedf07/1750-2187-4-4-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7080/2720935/a20db4560db5/1750-2187-4-4-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7080/2720935/3c86e04cf552/1750-2187-4-4-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7080/2720935/676379e8bd20/1750-2187-4-4-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7080/2720935/ecd40db198fb/1750-2187-4-4-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7080/2720935/9dd1b4aedf07/1750-2187-4-4-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7080/2720935/a20db4560db5/1750-2187-4-4-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7080/2720935/3c86e04cf552/1750-2187-4-4-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7080/2720935/676379e8bd20/1750-2187-4-4-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7080/2720935/ecd40db198fb/1750-2187-4-4-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7080/2720935/9dd1b4aedf07/1750-2187-4-4-5.jpg

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