Network-based analysis implies critical roles of microRNAs in the long-term cellular responses to gold nanoparticles.

Since gold nanoparticles (AuNPs) have great potential to bring improvements to the biomedical field, their impact on biological systems should be better understood, particularly over the long term, using realistic doses of exposure. MicroRNAs (miRNAs) are small noncoding RNAs that play key roles in the regulation of biological pathways, from development to cellular stress responses. In this study, we performed genome-wide miRNA expression profiling in primary human dermal fibroblasts 20 weeks after chronic and acute (non-chronic) treatments to four AuNPs with different shapes and surface chemistries at a low dose. The exposure condition and AuNP surface chemistry had a significant impact on the modulation of miRNA levels. In addition, a network-based analysis was employed to provide a more complex, systems-level perspective of the miRNA expression changes. In response to the stress caused by AuNPs, miRNA co-expression networks perturbed in cells under non-chronic exposure to AuNPs were enriched for target genes implicated in the suppression of proliferative pathways, possibly in attempt to restore cell homeostasis, while changes in miRNA co-expression networks enriched for target genes related to activation of proliferative and suppression of apoptotic pathways were observed in cells chronically exposed to one specific type of AuNPs. In this case, miRNA dysregulation might be contributing to enforce a new cell phenotype during stress. Our findings suggest that miRNAs exert critical roles in the cellular responses to the stress provoked by a low dose of NPs in the long term and provide a fertile ground for further targeted experimental studies.