Sphingosine 1-phosphate regulates matrix metalloproteinase-9 expression and breast cell invasion through S1P3-Gαq coupling
Sphingosine 1-phosphate regulates matrix metalloproteinase-9 expression and breast cell invasion through S1P3-Gαq coupling
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DOI：
10.1242/jcs.076794
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发表时间：
2011-07-01
影响因子：
4
通讯作者：
Moon, Aree
中科院分区：
文献类型：
--
作者：
Kim, Eun-Sook;Kim, Jong-Sook;Moon, Aree
最近的证据表明炎症与乳腺癌的恶性进展有关。 1-磷酸鞘氨醇 (S1P) 作用于 G 蛋白偶联受体，被称为有效的炎症介质。在本研究中，研究了炎症脂质S1P对MCF10A人乳腺上皮细胞侵袭/迁移表型调节的影响，以阐明炎症与乳腺细胞侵袭性控制之间的因果关系。我们发现，S1P 在体外和体内均可诱导基质金属蛋白酶 9 (MMP-9)，从而增强侵袭和迁移。我们还表明 fos 在 S1P 对 MMP-9 的转录激活中起着至关重要的作用。此外，细胞外信号调节激酶 1 和 2 (ERK1/2)、p38 和 α 丝氨酸/苏氨酸蛋白激酶 (Akt) 的激活参与 S1P 介导的 MMP-9 表达和侵袭诱导过程。 S1P 诱导的侵袭/迁移反应需要激活 S1P 受体 S1P(3) 和 G(α q)，这表明 S1P 介导的侵袭性增强是由 S1P(3) 与异源三聚体 G(α q) 亚基的特异性偶联触发的。 S1P 诱导的 MMP-9 上调需要磷脂酶 C-β(4) 的激活和细胞内 Ca2+ 的释放。综上所述，本研究证明S1P通过MCF10A细胞中S1P(3)和G(alpha q)的偶联来调节MMP-9的诱导和侵袭，从而为S1P在促进乳腺细胞侵袭中的关键作用提供了分子基础。
Recent evidence suggests that inflammation is involved in malignant progression of breast cancer. Sphingosine 1-phosphate (S1P), acting on the G-protein-coupled receptors, is known as a potent inflammatory mediator. In this study, the effect of the inflammatory lipid S1P on the regulation of invasive/migratory phenotypes of MCF10A human breast epithelial cells was investigated to elucidate a causal relationship between inflammation and the control of invasiveness of breast cells. We show that S1P causes induction of matrix metalloproteinase-9 (MMP-9) in vitro and in vivo, and thus enhances invasion and migration. We also show that fos plays a crucial role in the transcriptional activation of MMP-9 by S1P. In addition, activation of extracellular-signal-regulated kinases 1 and 2 (ERK1/2), p38 and alpha serine/threonine-protein kinase (Akt) are involved in the process of S1P-mediated induction of MMP-9 expression and invasion. Activation of the S1P receptor S1P(3) and G(alpha q) are required for S1P-induced invasive/migratory responses, suggesting that the enhancement of S1P-mediated invasiveness is triggered by the specific coupling of S1P(3) to the heterotrimeric G(alpha q) subunit. Activation of phospholipase C-beta(4) and intracellular Ca2+ release are required for S1P-induced MMP-9 upregulation. Taken together, this study demonstrated that S1P regulates MMP-9 induction and invasiveness through coupling of S1P(3) and G(alpha q) in MCF10A cells, thus providing a molecular basis for the crucial role of S1P in promoting breast cell invasion.