Kiratipaiboon Chayanin, Stueckle Todd A, Ghosh Rajib, Rojanasakul Liying W, Chen Yi Charlie, Dinu Cerasela Zoica, Rojanasakul Yon
Department of Pharmaceutical Sciences, West Virginia University, Morgantown, West Virginia, 26506, United States.
Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia, 26505, United States.
Environ Sci Nano. 2019 Jul 1;6(7):2152-2170. doi: 10.1039/C9EN00183B. Epub 2019 May 24.
Cancer stem cells (CSCs) are a key driver of tumor formation and metastasis, but how they are affected by nanomaterials is largely unknown. The present study investigated the effects of different carbon-based nanomaterials (CNMs) on neoplastic and CSC-like transformation of human small airway epithelial cells and determined the underlying mechanisms. Using a physiologically relevant exposure model (long-term/low-dose) with system validation using a human carcinogen, asbestos, we demonstrated that single-walled carbon nanotubes, multi-walled carbon nanotubes, ultrafine carbon black, and crocidolite asbestos induced particle-specific anchorage-independent colony formation, DNA-strand break, and p53 downregulation, indicating genotoxicity and carcinogenic potential of CNMs. The chronic CNM-exposed cells exhibited CSC-like properties as indicated by 3D spheroid formation, anoikis resistance, and CSC markers expression. Mechanistic studies revealed specific self-renewal and epithelial-mesenchymal transition (EMT)-related transcription factors that are involved in the cellular transformation process. Pathway analysis of gene signaling networks supports the role of SOX2 and SNAI1 signaling in CNM-mediated transformation. These findings support the potential carcinogenicity of high aspect ratio CNMs and identified molecular targets and signaling pathways that may contribute to the disease development.
癌症干细胞（CSCs）是肿瘤形成和转移的关键驱动因素，但它们如何受到纳米材料的影响在很大程度上尚不清楚。本研究调查了不同碳基纳米材料（CNMs）对人小气道上皮细胞肿瘤性和CSC样转化的影响，并确定了其潜在机制。使用具有生理相关性的暴露模型（长期/低剂量）并用人致癌物石棉进行系统验证，我们证明单壁碳纳米管、多壁碳纳米管、超细炭黑和青石棉可诱导颗粒特异性的非锚定依赖性集落形成、DNA链断裂和p53下调，表明CNMs具有遗传毒性和致癌潜力。长期暴露于CNMs的细胞表现出CSC样特性，如三维球体形成、失巢凋亡抗性和CSC标志物表达。机制研究揭示了参与细胞转化过程的特定自我更新和上皮-间质转化（EMT）相关转录因子。基因信号网络的通路分析支持SOX2和SNAI1信号在CNM介导的转化中的作用。这些发现支持了高纵横比CNMs的潜在致癌性，并确定了可能有助于疾病发展的分子靶点和信号通路。
