Rapid development and deployment of engineered nanomaterials, such as amorphous silica nanoparticles (SiNPs) in various commercial and biomedical applications have raised concerns about their potential adverse health effects, especially their chronic effects which have not been well addressed. In this study, human lung epithelial cells, BEAS-2B were continuously exposed to amorphous SiNPs, 5 μg/mL for 40 passages. We demonstrated here that prolonged exposure of BEAS-2B cells to amorphous SiNPs induced malignant transformation as indicated by enhanced cellular proliferation, anchorage-independent cell growth, and increased cell migration. The transformed cells induced tumorigenesis in nude mice. Furthermore, a comprehensive understanding of genome-wide transcriptional analysis was performed to clarify the molecular mechanisms based on microarray and bioinformatics analysis. Microarray data analysis demonstrated that chronic exposure of SiNPs affected expression of 821 genes, including 5 up-regulated and 816 down-regulated genes. Gene ontology and pathway analysis showed that SiNPs caused significant changes in gene expression patterns related to many important functions and pathways, mainly including response to cellular processes, oxidative stress, DNA damage, and cancer. In addition, Signal-net analysis indicated the most prominent significant role of tumor protein p53 in amorphous SiNPs-induced transformation. Further, data confirmed the inactivated p53 and aberrant p53 signaling under chronic amorphous SiNPs exposure. In summary, our data firstly demonstrated chronically low-dose amorphous SiNPs exposure resulted in malignant transformation of human lung epithelial cell via p53 signaling, which provides new in vitro evidence for the carcinogenicity of amorphous SiNPs.

中文翻译：

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非晶态二氧化硅纳米粒子通过P53信号传导诱导人肺上皮细胞恶性转化和肿瘤发生

工程纳米材料（例如无定形二氧化硅纳米颗粒（SiNPs））在各种商业和生物医学应用中的快速开发和部署引起了人们对其潜在的不利健康影响，尤其是其长期影响的关注，而这种不良影响尚未得到很好的解决。在这项研究中，人类肺上皮细胞BEAS-2B连续暴露于5μg/ mL的无定形SiNP中40次。我们在这里证明了BEAS-2B细胞长时间暴露于无定形SiNPs会诱导恶性转化，这可以通过增强细胞增殖，不依赖锚定的细胞生长和增加细胞迁移来表明。转化的细胞在裸鼠中诱导肿瘤发生。此外，对全基因组转录分析进行了全面的了解，以阐明基于微阵列和生物信息学分析的分子机制。微阵列数据分析表明，长期暴露于SiNPs会影响821个基因的表达，其中包括5个上调基因和816个下调基因。基因本体论和途径分析表明，SiNPs引起与许多重要功能和途径有关的基因表达模式的重大变化，主要包括对细胞过程的响应，氧化应激，DNA损伤和癌症。此外，Signal-net分析表明肿瘤蛋白p53在无定形SiNPs诱导的转化中最显着的重要作用。此外，数据证实了在慢性无定形SiNPs暴露下失活的p53和异常的p53信号传导。总之，通过p53信号传导，这为非晶SiNPs的致癌性提供了新的体外证据。