Monocyte chemoattractant protein-1 (MCP-1)/CCL2 secreted by hepatic myofibroblasts promotes migration and invasion of human hepatoma cells
Monocyte chemoattractant protein-1 (MCP-1)/CCL2 secreted by hepatic myofibroblasts promotes migration and invasion of human hepatoma cells
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DOI：
10.1002/ijc.24800
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发表时间：
2010-03-01
影响因子：
6.4
通讯作者：
Charnaux, Nathalie
中科院分区：
文献类型：
--
作者：
Dagouassat, Maylis;Suffee, Nadine;Charnaux, Nathalie
本研究的目的是探讨肌成纤维细胞和趋化因子单核细胞趋化蛋白-1（MCP-1）/CCL 2是否在肝细胞癌进展中发挥作用。我们观察到肝肌成纤维细胞LI 90表达MCP-1/CCL 2 mRNA并分泌这种趋化因子。此外，肌成纤维细胞LI 90细胞条件培养基（LI 90-CM）诱导人肝癌Huh 7细胞迁移和侵袭。当使用去除MCP-1/CCL 2的LI 90-CM时，这些作用会大大降低。我们发现，MCP-1/CCL 2诱导Huh 7细胞迁移和入侵，通过其G-蛋白偶联受体CCR 2，并在较小程度上，通过CCR 1只有在高MCP-1/CCL 2浓度。MCP-1/CCL 2的趋化活性依赖于粘着斑组分的酪氨酸磷酸化，并依赖于基质金属蛋白酶（MMP）-2和MMP-9。此外，我们观察到，Huh 7细胞迁移和入侵诱导的趋化因子强烈抑制肝素，β-D-木糖苷处理的细胞和抗多配体蛋白聚糖-1和-4抗体。最后，我们开发了一个三维共培养模型的肌成纤维细胞LI 90和Huh 7细胞，并证明MCP-1/CCL 2和它的膜伴侣，CCR 1和CCR 2，可能参与混合肝癌肌成纤维细胞球体的形成。总之，我们的数据表明，人肝肌成纤维细胞作用于肝癌细胞的旁分泌方式，以增加其侵袭性，并表明肌成纤维细胞衍生的MCP-1/CCL 2可能参与肝细胞癌的发病机制。
The aim of our study was to investigate whether myofibroblasts and the chemokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 may play a role in hepatocellular carcinoma progression. We observed that hepatic myofibroblast LI90 cells express MCP-1/CCL2 mRNA and secrete this chemokine. Moreover, myofibroblast LI90 cell-conditioned medium (LI90-CM) induces human hepatoma Huh7 cell migration and invasion. These effects are strongly reduced when a MCP-1/CCL2-depleted LI90-CM was used. We showed that MCP-1/CCL2 induces Huh7 cell migration and invasion through its G-protein-coupled receptor CCR2 and, to a lesser extent, through CCR1 only at high MCP-1/CCL2 concentrations. MCP-1/CCL2's chemotactic activities rely on tyrosine phosphorylation of focal adhesion components and depend on matrix metalloproteinase (MMP)-2 and MMP-9. Furthermore, we observed that Huh7 cell migration and invasion induced by the chemokine are strongly inhibited by heparin, by beta-D-xyloside treatment of cells and by anti-syndecan-1 and -4 antibodies. Finally, we developed a 3-dimensional coculture model of myofibroblast LI90 and Huh7 cells and demonstrated that MCP-1/CCL2 and its membrane partners, CCR1 and CCR2, may be involved in the formation of mixed hepatoma-myofibroblast spheroids. In conclusion, our data show that human liver myofibroblasts act on hepatoma cells in a paracrine manner to increase their invasiveness and suggest that myofibroblast-derived MCP-1/CCL2 could be involved in the pathogenesis of hepatocellular carcinoma.