Department of Pharmaceutical Sciences, West Virginia University Morgantown, WV, USA.
Health Effects Laboratory Division, Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health Morgantown, WV, USA.
Front Physiol. 2014 Jun 12;5:222. doi: 10.3389/fphys.2014.00222. eCollection 2014.
Rapid development and deployment of engineered nanomaterials such as carbon nanotubes (CNTs) in various commercial and biomedical applications have raised concerns about their potential adverse health effects, especially their long-term effects which have not been well addressed. We demonstrated here that prolonged exposure of human mesothelial cells to single-walled CNT (SWCNT) induced neoplastic-like transformation as indicated by anchorage-independent cell growth and increased cell invasiveness. Such transformation was associated with an up-regulation of H-Ras and activation of ERK1/2. Downregulation of H-Ras by siRNA or inactivation of ERK by chemical inhibitor effectively inhibited the aggressive phenotype of SWCNT-exposed cells. Integrin alpha V and cortactin, but not epithelial-mesenchymal transition (EMT) transcriptional regulators, were up-regulated in the SWCNT-exposed cells, suggesting their role in the aggressive phenotype. Cortactin expression was shown to be controlled by the H-Ras/ERK signaling. Thus, our results indicate a novel role of H-Ras/ERK signaling and cortactin in the aggressive transformation of human mesothelial cells by SWCNT.
在各种商业和生物医学应用中，工程纳米材料（如碳纳米管 [CNT]）的快速发展和应用引发了人们对其潜在不良健康影响的担忧，尤其是对其尚未得到充分解决的长期影响的担忧。我们在这里证明，人胸膜细胞长期暴露于单壁 CNT（SWCNT）会导致类似于肿瘤的转化，表现为非锚定依赖性细胞生长和细胞侵袭性增加。这种转化与 H-Ras 的上调和 ERK1/2 的激活有关。通过 siRNA 下调 H-Ras 或用化学抑制剂失活 ERK 可有效抑制 SWCNT 暴露细胞的侵袭表型。整合素 α V 和桩蛋白在 SWCNT 暴露的细胞中上调，而不是上皮-间充质转化（EMT）转录调节剂，表明它们在侵袭表型中的作用。桩蛋白的表达受 H-Ras/ERK 信号的控制。因此，我们的结果表明，H-Ras/ERK 信号和桩蛋白在 SWCNT 诱导的人胸膜细胞侵袭性转化中发挥了新的作用。
