Gaseous Nitrogen Oxide Promotes Human Lung Cancer Cell Line A549 Migration, Invasion, and Metastasis via iNOS-Mediated MMP-2 Production
Gaseous Nitrogen Oxide Promotes Human Lung Cancer Cell Line A549 Migration, Invasion, and Metastasis via iNOS-Mediated MMP-2 Production
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DOI：
10.1093/toxsci/kfn195
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发表时间：
2008-12-01
影响因子：
3.8
通讯作者：
Wang, Chau-Jong
中科院分区：
文献类型：
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作者：
Chen, Jing-Hsien;Lin, Hui-Hsuan;Wang, Chau-Jong
气态氮氧化物（gNO）是一种重要的室内外空气污染物。许多研究表明，gNO通过其氧化特性和自由基引起肺组织损伤。然而，有相当少的数据之间的关联肺癌和gNO暴露。本研究的目的是检查gNO是否有助于肺癌的恶性进展过程。伤口愈合实验和体外transwell实验结果表明，在非细胞毒性浓度下，gNO诱导人肺癌细胞A549迁移和侵袭的作用呈剂量和时间依赖性。gNO能够诱导NO从A549细胞中释放，在相同的治疗期间，这种作用是通过激活诱导型一氧化氮合酶（iNOS）介导的，但不是组成型亚型。gNO处理后，基质金属蛋白酶（MMP）的表达增加，同时金属蛋白酶-2的抑制组织抑制剂的减少。gNO介导的MMP-2诱导似乎是核因子κ B和活化蛋白-1活化的结果，因为它们的DNA结合活性被gNO增强。NOS抑制剂（N-G-nitro-L-arginine methyl ester）预处理可有效地抑制gNO的上述作用。使用小鼠模型，我们表明，gNO促进A549转移到肺通过一种机制，涉及iNOS依赖性MMP-2的活性。我们的数据表明，gNO暴露，这反过来又导致iNOS激活和MMP介导的细胞事件的增强，与肺癌的发展。
Gaseous nitrogen oxide (gNO) is an important indoor and outdoor air pollutant. Many studies have indicated gNO causes lung tissue damage by its oxidation properties and free radicals. However, there are considerably few data on the association between lung cancer and gNO exposure. The purpose of this study was to examine whether gNO could contribute to the process of malignant progression of lung cancer. The results of wound-healing assay and in vitro transwell assay revealed that gNO-induced dose and time dependently the migration and invasion of A549 cells, a human lung cancer cell line, under noncytotoxic concentrations. gNO was able to induce release of NO from A549 cells, an effect that was mediated via the activation of inducible nitric oxide synthases (iNOS), but not constitutive isoforms, during the same treatment period. An increased expression of matrix metalloproteinase (MMP) and a coincided reduction in repress tissue inhibitors of metalloprotease-2 were observed upon the treatment of gNO. The gNO-mediated MMP-2 induction appeared to be a consequence of nuclear factor kappa B and activation protein-1 activation, because that their DNA binding activity was enhanced by gNO. All these influences of gNO were efficiently repressed by the pretreatment of a NOS inhibitor (N-G-nitro-L-arginine methyl ester). Using a mouse model, we showed that gNO promoted A549 metastasis to the lung through a mechanism involving the iNOS-dependent MMP-2 activity. Our data imply that gNO exposure, which in turn led to iNOS activation and the enhancement of MMP-mediated cellular events, was related to lung cancer development.