TIMP-1 mediates the inhibitory effect of interleukin-6 on the proliferation of a hepatocarcinoma cell line in a STAT3-dependent manner
TIMP-1 mediates the inhibitory effect of interleukin-6 on the proliferation of a hepatocarcinoma cell line in a STAT3-dependent manner
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TIMP-1以STAT3依赖性方式介导白细胞介素6对肝癌细胞系增殖的抑制作用
DOI：
10.1590/s0100-879x2007000500004
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发表时间：
2007-05-01
影响因子：
2.3
通讯作者：
Li, C.-J.
中科院分区：
文献类型：
--
作者：
Guo, S.-Y.;Shen, X.;Li, C.-J.
金属蛋白酶组织抑制剂(TIMP)-1是一种多功能蛋白，它不仅是基质金属蛋白酶(MMP)的抑制剂，而且还具有可能的“细胞因子样”作用。在这里，我们首先使用实时定量 RT-PCR 比较了 BEL-7402（肝细胞癌细胞系）、L-02（正常肝细胞系）和 QSG-7701（源自肝癌外周组织的细胞系）中 TIMP-1 和 MMP-9 的 mRNA 表达。通过评估 MMP-9/TIMP-1 比率的变化作为两个基因表达相互变化的指标，我们观察到 BEL-7402 中的 MMP-9/TIMP-1 比率分别比 L-02 和 QSG-7701 中高约 13 倍和 5 倍。值得注意的是，TIMP-1 的过表达降低了 BEL-7402 中 MMP-9/TIMP-1 的比率，然后将细胞生长抑制至 60%，并将迁移减少至约 30%。同时，我们的数据显示白介素6（IL-6）（100 ng/mL）也可以抑制BEL-7402的细胞生长。进一步的研究表明，TIMP-1以STAT3依赖性方式介导IL-6对BEL-7402细胞增殖的抑制作用，从而可以进一步加速细胞周期蛋白依赖性激酶抑制剂p21的表达。显性失活 STAT3 突变体完全消除了 IL-6 诱导的 TIMP-1 表达及其生物学功能。目前的结果表明，TIMP-1可能是调节IL-6对BEL-7402增殖抑制作用的介质之一，其中STAT3信号转导和p21上调也发挥着重要作用。
The tissue inhibitor of metalloproteinases (TIMP)-1 is a multifunctional protein which is not only an inhibitor of matrix metalloproteinases (MMPs) but also to have a possible '' cytokine-like '' action. Here, we first compared mRNA expression of TIMP-1 and MMP-9 in BEL-7402 ( a hepatocellular carcinoma cell line), L-02 (a normal liver cell line) and QSG-7701 ( a cell line derived from peripheral tissue of liver carcinoma) using real-time quantitative RT-PCR. By evaluating the variation of the MMP-9/ TIMP-1 ratio as an index of reciprocal changes of the expression of the two genes, we observed that the MMP-9/ TIMP-1 ratio was about 13-and 5-fold higher in BEL-7402 than in L-02 and QSG-7701, respectively. Significantly, overexpression of TIMP-1 decreased the MMP-9/ TIMP-1 ratio in BEL-7402 and then inhibited the cell growth to 60% and reduced the migration to about 30%. Meanwhile, our data showed that interleukin-6 (IL-6) (100 ng/mL) could also inhibited the cell growth of BEL-7402. Further studies indicated that TIMP-1 mediated the inhibitory effect of IL-6 on BEL-7402 cell proliferation in a STAT3-dependent manner, which could further accelerate the expression of the cyclin-dependent kinase inhibitor p21. A dominant negative STAT3 mutant totally abolished IL-6-induced TIMP-1 expression and its biological functions. The present results demonstrate that TIMP-1 may be one of the mediators that regulate the inhibitory effect of IL-6 on BEL-7402 proliferation in which STAT3 signal transduction and p21 up-regulation also play important roles.