Low-density lipoprotein receptor-related protein 1 promotes cancer cell migration and invasion by inducing the expression of matrix metalloproteinases 2 and 9.
Low-density lipoprotein receptor-related protein 1 promotes cancer cell migration and invasion by inducing the expression of matrix metalloproteinases 2 and 9.
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DOI：
10.1158/0008-5472.can-08-3379
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Bu G
中科院分区：
文献类型：
--
作者：
Song H;Li Y;Lee J;Schwartz AL;Bu G
低密度脂蛋白受体相关蛋白1（LRP 1）是一种多功能内吞受体，参与多种细胞外配体的代谢，包括在肿瘤侵袭中起关键作用的蛋白酶。尽管一些研究已经证明LRP 1在癌细胞中的表达增加，但其在肿瘤发展和进展中的功能仍不清楚。在这里，我们揭示了一种新的机制，LRP 1诱导基质金属蛋白酶2（MMP 2）和MMP 9的表达，从而促进人胶质母细胞瘤U87细胞的迁移和侵袭。LRP 1表达的敲低大大降低了U87细胞的迁移和侵袭，这是通过功能性LRP 1小受体的强制表达来拯救的。通过特异性拮抗剂RAP抑制配体与LRP 1的结合也导致癌细胞迁移和侵袭减少。由于基质金属蛋白酶在癌细胞迁移和侵袭中起着关键作用，我们检测了几种基质金属蛋白酶的表达，发现在LRP 1敲低细胞中，功能性基质金属蛋白酶2和基质金属蛋白酶9的表达选择性降低。更重要的是，降低的细胞迁移和侵袭LRP 1敲低细胞完全获救的MMP 2或MMP 9的外源性表达，这表明这些MMP可能是LRP 1介导的信号的下游目标。我们进一步表明，磷酸化ERK的水平显着降低LRP 1沉默的细胞，这表明ERK是一个潜在的介质LRP 1调节MMP 2和MMP 9的表达在U87细胞。总之，我们的数据有力地表明，LRP 1促进胶质母细胞瘤细胞的迁移和侵袭，通过调节MMP 2和MMP 9的表达和功能，可能通过ERK依赖的信号通路。
The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor involved in the metabolism of various extracellular ligands including proteinases that play critical roles in tumor invasion. Although several studies have demonstrated an increased expression of LRP1 in cancer cells, its function in tumor development and progression remains largely unclear. Here, we reveal a novel mechanism by which LRP1 induces the expression of matrix metalloproteinase 2 (MMP2) and MMP9 and thereby promotes the migration and invasion of human glioblastoma U87 cells. Knockdown of LRP1 expression greatly decreased U87 cell migration and invasion, which was rescued by forced expression of a functional LRP1 minireceptor. Inhibition of ligand binding to LRP1 by a specific antagonist RAP also led to reduced cancer cell migration and invasion. Because MMPs play critical roles in cancer cell migration and invasion, we examined the expression of several MMPs and found that the expression of functional MMP2 and MMP9 was selectively decreased in LRP1-knockdown cells. More importantly, decreased cell migration and invasion of LRP1-knockdown cells were completely rescued by exogenous expression of MMP2 or MMP9, suggesting that these MMPs are likely downstream targets of LRP1-mediated signaling. We further show that the level of phosphorylated ERK was significantly decreased in LRP1-silenced cells, suggesting that ERK is a potential mediator of LRP1-regulated MMP2 and MMP9 expression in U87 cells. Together, our data strongly suggest that LRP1 promotes glioblastoma cell migration and invasion by regulating the expression and function of MMP2 and MMP9 perhaps via an ERK-dependent signaling pathway.