Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
J Biomed Mater Res A. 2020 May;108(7):1520-1533. doi: 10.1002/jbm.a.36923. Epub 2020 Mar 31.
Understanding the cellular and molecular toxicity of graphene and its derivatives is essential for their biomedical applications. Herein, gene expression profile of graphene-exposed cells was retrieved from the Gene expression omnibus database. Differentially expressed genes and their functional roles were then investigated through the pathway, protein-protein interaction (PPI) network, and module analysis. High degree (hub) and high betweenness centrality (bottleneck) nodes were subsequently identified. The functional analysis of central genes indicated that these graphene-gene interactions could be of great value for further investigation. Accordingly, we also followed the expression of five hub-bottleneck genes in graphene-treated murine peritoneal macrophages and human breast cancer cell line by real-time PCR. The five hub-bottleneck genes related to graphene cytotoxicity; CDK1, CCNB1, PLK1, TOP2A, and CCNA2 were identified through network analysis, which were highly correlated with regulation of cell cycle processes. The module analysis indicated the cell cycle pathway to be the predominant one. Gene expression evaluation showed downregulation of these genes in the macrophages and cancer cells treated with graphene. These results provided some new intuitions concerning the graphene-cell interactions and unveiled targeting critical cell cycle regulators. The present study indicated some toxic effects of graphene-based materials through systems toxicology assessment. Integrating gene expression and PPI network may help explaining biological responses of graphene and lead to beneficial impacts in nanomedicine.
了解石墨烯及其衍生物的细胞和分子毒性对于它们的生物医学应用至关重要。本文从基因表达综合数据库中检索了暴露于石墨烯的细胞的基因表达谱。然后通过途径、蛋白质-蛋白质相互作用（PPI）网络和模块分析研究了差异表达基因及其功能作用。随后鉴定了高度（枢纽）和高介数中心性（瓶颈）节点。中心基因的功能分析表明，这些石墨烯-基因相互作用对于进一步研究具有重要价值。因此，我们还通过实时 PCR 检测了石墨烯处理的鼠腹膜巨噬细胞和人乳腺癌细胞系中五个枢纽-瓶颈基因的表达。通过网络分析鉴定了与石墨烯细胞毒性相关的五个枢纽-瓶颈基因，即 CDK1、CCNB1、PLK1、TOP2A 和 CCNA2，它们与细胞周期过程的调节密切相关。模块分析表明细胞周期途径是主要途径。基因表达评估表明，在巨噬细胞和癌细胞中，这些基因在石墨烯处理后下调。这些结果为石墨烯-细胞相互作用提供了一些新的见解，并揭示了靶向关键细胞周期调节剂的可能性。本研究通过系统毒理学评估表明了基于石墨烯的材料的一些毒性作用。整合基因表达和 PPI 网络可能有助于解释石墨烯的生物学反应，并为纳米医学带来有益影响。
