A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4
A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4
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DOI：
10.1038/onc.2013.568
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发表时间：
2015-01-22
期刊：
影响因子：
8
通讯作者：
Grigorian, M.
中科院分区：
文献类型：
--
作者：
Hansen, M. T.;Forst, B.;Grigorian, M.
S100 A4与转移和慢性炎症有关，但其功能仍不确定。在这里，我们建立了炎症和转移性肿瘤进展之间的S100 A4依赖性联系。我们发现急性相反应蛋白血清淀粉样蛋白A（SAA）1和SAA 3是S100 A4通过Toll样受体4（TLR 4）/核因子-κ B信号转导的转录靶点。SAA蛋白刺激RANTES（在活化后调节正常T细胞表达和可能分泌）、G-CSF（粒细胞集落刺激因子）和MMP 2（基质金属蛋白酶2）、MMP 3、MMP 9和MMP 13的转录。我们还首次表明SAA刺激其自身的转录以及促炎S100 A8和S100 A9蛋白的转录。此外，它们强烈增强肿瘤细胞与纤连蛋白的粘附，并刺激人和小鼠肿瘤细胞的迁移和侵袭。腹腔注射S100 A4蛋白可诱导SAA蛋白和细胞因子以器官特异性方式表达。在乳腺癌动物模型中，肿瘤细胞中SAA 1或SAA 3的异位表达有力地促进了广泛的转移形成，伴随着免疫细胞的大量浸润。此外，S100 A4和SAA在来自结直肠癌患者的肿瘤样品中的协调表达与总生存率降低显著相关。这些数据表明，SAA蛋白是S100 A4的转移促进功能的效应子，并作为炎症和肿瘤进展之间的联系。
S100A4 is implicated in metastasis and chronic inflammation, but its function remains uncertain. Here we establish an S100A4-dependent link between inflammation and metastatic tumor progression. We found that the acute-phase response proteins serum amyloid A (SAA) 1 and SAA3 are transcriptional targets of S100A4 via Toll-like receptor 4 (TLR4)/nuclear factor-kappa B signaling. SAA proteins stimulated the transcription of RANTES (regulated upon activation normal T-cell expressed and presumably secreted), G-CSF (granulocyte-colony-stimulating factor) and MMP2 (matrix metalloproteinase 2), MMP3, MMP9 and MMP13. We have also shown for the first time that SAA stimulate their own transcription as well as that of proinflammatory S100A8 and S100A9 proteins. Moreover, they strongly enhanced tumor cell adhesion to fibronectin, and stimulated migration and invasion of human and mouse tumor cells. Intravenously injected S100A4 protein induced expression of SAA proteins and cytokines in an organ-specific manner. In a breast cancer animal model, ectopic expression of SAA1 or SAA3 in tumor cells potently promoted widespread metastasis formation accompanied by a massive infiltration of immune cells. Furthermore, coordinate expression of S100A4 and SAA in tumor samples from colorectal carcinoma patients significantly correlated with reduced overall survival. These data show that SAA proteins are effectors for the metastasis-promoting functions of S100A4, and serve as a link between inflammation and tumor progression.