Nano silicon dioxide (Nano-SiO₂) has been widely used in industries such as the field of biomedical engineering. Despite the existing evidence that Nano-SiO₂ exposure could induce oxidative stress and inflammatory responses in multiple organ systems, the carcinogenicity of Nano-SiO₂ exposure has rarely been investigated. Thus in this study, two types of human bronchial epithelial cell lines (16HBE and BEAS-2B) were selected as in vitro models to investigate the carcinogenicity of Nano-SiO₂. Our results revealed that Nano-SiO₂ induces a malignant cellular transformation in human bronchial epithelial cells according to the soft agar colony formation assay. The carcinogenesis induced by Nano-SiO₂ was also confirmed in nude mice. By using immunofluorescence assay and high-performance capillary electrophoresis (HPCE), we observed a genome-wide DNA hypomethylation induced by Nano-SiO₂. Besides the reduced enzyme activity of total DNMTs upon Nano-SiO₂ treatment, altered expression of DNMTs and methyl-CpG binding proteins were observed. Besides, we found that the expression of NRF2 was activated by demethylation of CpG islands within the NRF2 promoter region and the overexpression of NRF2 could alleviate the carcinogenesis induced by Nano-SiO₂. Taken together, our results suggested that Nano-SiO₂ induces malignant cellular transformation with a global DNA hypomethylation, and the demethylation of NRF2 promoter activates the expression of NRF2, which plays an important role in protecting against the carcinogenesis induced by Nano-SiO₂.

纳米二氧化硅（Nano-SiO ₂）已广泛用于诸如生物医学工程领域的工业中。尽管已有证据表明纳米SiO ₂暴露可在多个器官系统中诱导氧化应激和炎症反应，但很少研究纳米SiO ₂暴露的致癌性。因此，在本研究中，选择了两种类型的人支气管上皮细胞系（16HBE和BEAS-2B）作为体外模型研究纳米SiO ₂的致癌性。我们的结果表明，根据软琼脂菌落形成试验，纳米SiO ₂诱导人支气管上皮细胞发生恶性细胞转化。在裸鼠中也证实了纳米SiO ₂诱导的致癌作用。通过使用免疫荧光测定和高效毛细管电泳（HPCE），我们观察到了纳米SiO ₂诱导的全基因组DNA甲基化不足。除了纳米SiO ₂降低了总DNMT的酶活性在治疗中，观察到DNMT和甲基-CpG结合蛋白的表达发生了改变。此外，我们发现NRF2的表达被NRF2启动子区域内CpG岛的去甲基化激活，并且NRF2的过表达可以减轻Nano-SiO ₂诱导的致癌作用。综上所述，我们的研究结果表明，纳米SiO ₂诱导了具有整体DNA低甲基化的恶性细胞转化，而NRF2启动子的去甲基化激活了NRF2的表达，这在预防纳米SiO ₂诱导的癌变中起着重要作用。