Department of Pharmaceutical Sciences and Mary Babb Randolph Cancer Center, ‡Department of Chemical Engineering, and §Department of Computer Science and Electrical Engineering, West Virginia University , Morgantown, West Virginia 26506, United States.
ACS Nano. 2013 Sep 24;7(9):7711-23. doi: 10.1021/nn402241b. Epub 2013 Aug 12.
Malignant mesothelioma is one of the most aggressive forms of cancer known. Recent studies have shown that carbon nanotubes (CNTs) are biopersistent and induce mesothelioma in animals, but the underlying mechanisms are not known. Here, we investigate the effect of long-term exposure to high aspect ratio CNTs on the aggressive behaviors of human pleural mesothelial cells, the primary cellular target of human lung mesothelioma. We show that chronic exposure (4 months) to single- and multiwalled CNTs induced proliferation, migration, and invasion of the cells similar to that observed in asbestos-exposed cells. An up-regulation of several key genes known to be important in cell invasion, notably matrix metalloproteinase-2 (MMP-2), was observed in the exposed mesothelial cells as determined by real-time PCR. Western blot and enzyme activity assays confirmed the increased expression and activity of MMP-2. Whole genome microarray analysis further indicated the importance of MMP-2 in the invasion gene signaling network of the exposed cells. Knockdown of MMP-2 in CNT and asbestos-exposed cells by shRNA-mediated gene silencing effectively inhibited the aggressive phenotypes. This study demonstrates CNT-induced cell invasion and indicates the role of MMP-2 in the process.
恶性间皮瘤是已知的最具侵袭性的癌症之一。最近的研究表明，碳纳米管（CNT）具有生物持久性，并在动物中诱导间皮瘤，但潜在的机制尚不清楚。在这里，我们研究了长期暴露于高纵横比 CNT 对人类胸膜间皮细胞侵袭行为的影响，间皮细胞是人类肺间皮瘤的主要细胞靶标。我们发现，单壁和多壁 CNT 的慢性暴露（4 个月）诱导细胞增殖、迁移和侵袭，类似于暴露于石棉的细胞中观察到的情况。通过实时 PCR 检测到暴露的间皮细胞中几个已知在细胞侵袭中重要的关键基因的上调，特别是基质金属蛋白酶-2（MMP-2）。Western blot 和酶活性测定进一步证实了 MMP-2 的表达和活性增加。全基因组微阵列分析进一步表明 MMP-2 在暴露细胞的侵袭基因信号网络中的重要性。通过 shRNA 介导的基因沉默敲低 CNT 和石棉暴露细胞中的 MMP-2 可有效抑制侵袭表型。这项研究证明了 CNT 诱导的细胞侵袭，并表明 MMP-2 在该过程中的作用。
