Aspirin inhibits tumor cell invasiveness induced by Epstein-Barr virus latent membrane protein 1 through suppression of matrix metalloproteinase-9 expression.
Aspirin inhibits tumor cell invasiveness induced by Epstein-Barr virus latent membrane protein 1 through suppression of matrix metalloproteinase-9 expression.
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DOI：
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发表时间：
2000-05
期刊：
影响因子：
11.2
通讯作者：
S. Murono;T. Yoshizaki;Hiroshi Sato;H. Takeshita;M. Furukawa;Joseph S. Pagano
中科院分区：
文献类型：
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作者：
S. Murono;T. Yoshizaki;Hiroshi Sato;H. Takeshita;M. Furukawa;Joseph S. Pagano
基质金属蛋白酶（MMP）被认为在肿瘤侵袭和转移中发挥着至关重要的作用。因为我们已经证明 EBV 潜伏膜蛋白 1 (LMP1) 通过激活核因子 (NF)-kappaB 和激活蛋白 (AP)-1 来增强 MMP-9 表达 (T. Yoshizaki 等，Proc. Natl. Acad. Sci. USA, 95: 3621-3626, 1998)，因此我们测试了 LMP1 对 MMP-9 的上调是否可能相关增强肿瘤细胞的体外侵袭能力。还测试了阿司匹林和水杨酸钠是否可以降低裸鼠肿瘤的侵袭性以及LMP1是否可以增强MMP-9的表达。与载体转染的C33A细胞相比，稳定表达LMP1的C33A细胞的MMP-9表达增加，并且通过重建基底膜表现出更大的侵袭力（P < 0.02）。阿司匹林或水杨酸钠治疗可抑制表达 LMP1 的 C33A 细胞的侵袭性 (P < 0.03)，并抑制酶谱分析中 LMP1 诱导的 MMP-9 表达和 CAT 报告基因测定中 LMP1 诱导的 MMP-9 启动子活性 (P < 0.01)。内源性 MMP-2 水平不受这两种药物的影响。两种药物均将截短的 MMP-9 启动子构建体（仅包含 AP-1 的结合位点）的 CAT 活性抑制至基础水平（P < 0.05）。此外，EMSA 表明水杨酸盐的作用不仅是通过抑制 NF-κB，而且还通过抑制 AP-1 结合活性。 NF-kappaB 的 p50/p65 亚基或 c-Jun 过表达可以逆转水杨酸盐的抑制作用。阿司匹林对 NF-kappaB 活性的抑制作用归因于 IkappaB 激酶活性的抑制。最后，与源自载体转染的C33A细胞的肿瘤相比，源自在裸鼠中生长的稳定表达LMP1的C33A细胞的肿瘤显示出增强的MMP-9水平。这种增强作用被阿司匹林治疗小鼠所抑制。这些结果表明，阿司匹林可能能够通过抑制 MMP-9 来抑制表达 LMP1 的 EBV 相关肿瘤的侵袭和转移。
Matrix metalloproteinases (MMPs) are thought to play crucial roles in tumor invasion and metastasis. Because we have shown that EBV latent membrane protein 1 (LMP1) enhances MMP-9 expression by activation of nuclear factor (NF)-kappaB and activator protein (AP)-1 (T. Yoshizaki, et al., Proc. Natl. Acad. Sci. USA, 95: 3621-3626, 1998), we therefore tested whether up-regulation of MMP-9 by LMP1 could be correlated with enhanced invasiveness of tumor cells in vitro. Whether aspirin and sodium salicylate could reduce invasiveness and whether LMP1 could enhance MMP-9 expression in tumors grown in nude mice were also tested. C33A cells stably expressing LMP1 had increased expression of MMP-9 and showed greater invasion through reconstituted basement membrane compared with vector-transfected C33A cells (P < 0.02). Treatment with aspirin or sodium salicylate inhibited invasiveness of the LMP1-expressing C33A cells (P < 0.03) and suppressed both the LMP1-induced MMP-9 expression in zymographic analyses and LMP1-induced MMP-9 promoter activity in CAT reporter assays (P < 0.01). Endogenous MMP-2 levels were unaffected by either drug. Both drugs repressed the CAT activity of the truncated MMP-9 promoter construct, which only contained a binding site for AP-1, to the basal level (P < 0.05). Moreover, EMSA indicated that the effects of the salicylates were through the inhibition of not only NF-kappaB but also AP-1 binding activity. Inhibitory effect of salicylates could be reversed by p50/p65 subunits of NF-kappaB or c-Jun overexpression. The inhibitory effect of aspirin on NF-kappaB activity was attributable to the inhibition of IkappaB kinase activity. Finally, tumors derived from C33A cells stably expressing LMP1 grown in nude mice showed enhanced MMP-9 levels compared with tumors derived from vector-transfected C33A cells. This enhancement was inhibited by treatment of the mice with aspirin. These results suggest that aspirin may be able to suppress invasion and metastasis of EBV-associated tumors that express LMP1 by suppression of MMP-9.