A cross-cancer differential co-expression network reveals microRNA-regulated oncogenic functional modules.

MicroRNAs (miRNAs) are small non-coding RNAs that can regulate their target gene expressions at the post-transcriptional level. Moreover, they have been reported as either oncomirs or tumor suppressors and possess therapeutic potential in cancer. In this study, we investigated differential co-expression of miRNAs across four cancer types. We observed that the loss of positive co-expressions among miRNAs frequently occurs in the studied cancer types. This observation suggests that the disruption of positive co-expressions among miRNAs may be prevalent during tumorigenesis. By systematically collecting these lost positive co-expressions among miRNAs in cancer, we constructed a cross-cancer miRNA differential co-expression network. We observed that the influential miRNAs in the proposed network, i.e., hubs or in larger cliques, tended to be involved in more cancer types than other miRNAs. Moreover, we found that miRNAs which lose their positive co-expressions in cancers might co-contribute to cancer development, and even could be used to predict the cancer types in which miRNAs were involved. Finally, we identified two potential miRNA-regulated onco-modules, mitosis and DNA replication, that are associated with poor survival outcomes in patients across multiple cancers. Collectively, our study suggested that the disruption of miRNA positive co-expression in cancer might contribute to cancer development. Our findings also form an important basis for identifying miRNAs with potential co-contribution to carcinogenesis.