The Serine Protease Inhibitor Protease Nexin-1 Controls Mammary Cancer Metastasis through LRP-1-Mediated MMP-9 Expression
The Serine Protease Inhibitor Protease Nexin-1 Controls Mammary Cancer Metastasis through LRP-1-Mediated MMP-9 Expression
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DOI：
10.1158/0008-5472.can-08-4573
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发表时间：
2009-07-15
期刊：
影响因子：
11.2
通讯作者：
Monard, Denis
中科院分区：
文献类型：
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作者：
Fayard, Berengere;Bianchi, Fabrizio;Monard, Denis
蛋白酶通过降解细胞外基质的能力，介导癌细胞的侵袭和转移。矛盾的是，一些丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶）经常在人类肿瘤中过度表达。通过计算分析，我们发现蛋白酶连接蛋白-1 （PN-1）的RNA水平在雌激素受体阴性和高级别乳腺癌中显著升高。PN-1是一种阻断多种蛋白酶活性的丝状蛋白。对两种乳腺癌细胞系（pn -1阴性的168FARN细胞和pn -1阳性的4T1细胞）的机制研究补充了计算机方法，这两种细胞系都形成原发性乳腺肿瘤，但只有4T1肿瘤能够转移到肺部。我们发现，用PN-1处理168FARN细胞，通过低密度脂蛋白受体相关蛋白-1 （LRP-1）结合刺激细胞外信号调节的激酶活化，导致基质金属蛋白酶(MMP)-9 RNA、蛋白和分泌活性增加。pn -1沉默的4T1细胞表达低水平的MMP-9。此外，向小鼠注射pn -1沉默细胞不影响4T1原发性乳腺肿瘤的生长；然而，肿瘤的转移潜力受损，这可以通过在PN-1沉默的4T1细胞中重新表达可溶性MMP-9来恢复。因此，利用乳腺肿瘤模型，我们描述了一种新的途径，即丝氨酸蛋白PN-1通过结合LRP-1刺激细胞外信号调节的激酶信号、MMP-9的表达和乳腺肿瘤的转移扩散。重要的是，一项对126名乳腺癌患者的分析显示，那些乳腺肿瘤中PN-1水平升高的患者在复发时发生肺转移的可能性明显更高，但不会转移到其他部位。这些结果提示PN-1可能成为乳腺癌的预后标志物。[癌症研究2009；69 (14): 5690 - 8]
Through their ability to degrade the extracellular matrix, proteases mediate cancer cell invasion and metastasis. Paradoxically, some serine protease inhibitors (serpins) are often overexpressed in human tumors. Using computational analysis, we found that the RNA level of protease nexin-1 (PN-1), a serpin that blocks numerous proteases activity, is significantly elevated in estrogen receptor-alpha-negative and in high-grade breast cancer. The in silico approach was complemented by mechanistic studies on two mammary cancer cell lines, the PN-1-negative 168FARN cells and the PN-1-positive 4T1 cells, both of which form primary mammary tumors, but only 4T1 tumors are able to metastasize to the lungs. We show that treatment of 168FARN cells with PN-1 stimulates extracellular signal-regulated kinase activation via low-density lipoprotein receptor-related protein-1 (LRP-1) binding, resulting in increased matrix metalloproteinase (MMP)-9 RNA, protein, and secreted activity. PN-1-silenced 4T1 cells express low MMP-9 levels. Moreover, injection of PN-1-silenced cells into mice did not affect 4T1 primary mammary tumor outgrowth; however, the tumors had impaired metastatic potential, which could be restored by reexpressing soluble MMP-9 in the PN-1 silenced 4T1 cells. Thus, using mammary tumor models, we describe a novel pathway whereby the serpin PN-1 by binding LRP-1 stimulates extracellular signal-regulated kinase signaling, MMP-9 expression, and metastatic spread of mammary tumors. Importantly, an analysis of 126 breast cancer patients revealed that those -whose breast tumors had elevated PN-1 levels had a significantly higher probability to develop lung metastasis, but not metastasis to other sites, on relapse. These results suggest that PN-1 might become a prognostic marker in breast cancer. [Cancer Res 2009;69(14):5690-8]