Deciphering the transcription factor-microRNA-target gene regulatory network associated with graphene oxide cytotoxicity

Abstract

Graphene oxide (GO) has recently emanated as a promising material in cancer treatment. To unveil the underlying mechanisms of microRNAs (miRNAs) and potential target genes involved in GO cytotoxicity, we firstly compiled GO-related miRNAs and genes in human cancer cell lines treated with GO from public databases and published works. Besides miRNAs as post-transcriptional regulators of gene expression, transcription factors (TFs) are also the main regulators at the transcriptional level. In the following, we explored the regulatory relationships between miRNAs, target genes, and TFs. Thereafter, a gene regulatory network consisting of GO-responsive miRNAs, GO-responsive genes, and known human TFs was constructed. Then, 3-node regulatory motif types were detected in the resulting network. Among them, miRNA-FFL (feed-forward loop) was identified as a significant motif type. A total of 184 miRNA-FFLs were found and merged to generate a regulatory sub-network. Pathway analysis of the resulting sub-network highlighted adherens junction, focal adhesion, and TGFβ signaling pathways as the major pathways that previous studies demonstrate them to be the affected pathways in GO-treated cells. Functional investigations displayed that miRNAs might be involved in the control of apoptosis through disruption of cell adhesion in response to cytotoxicity. Moreover, GO-cell interactions can lead to miRNA targeting of genes (i.e. Rac1 and RhoA) involved in the cytoskeleton assembly process. These specific toxic properties support biomedical applications of GO, especially for cancer therapy.