Survey of miRNA-miRNA cooperative regulation principles across cancer types

Cooperative regulation among multiple microRNAs (miRNAs) is a complex type of posttranscriptional regulation in human; however, the global view of the system-level regulatory principles across cancers is still unclear. Here, we investigated miRNA-miRNA cooperative regulatory landscape across 18 cancer types and summarized the regulatory principles of miRNAs. The miRNA-miRNA cooperative pan-cancer network exhibited a scale-free and modular architecture. Cancer types with similar tissue origins had high similarity in cooperative network structure and expression of cooperative miRNA pairs. In addition, cooperative miRNAs showed divergent properties, including higher expression, greater expression variation and a stronger regulatory strength towards targets and were likely to regulate cancer hallmark-related functions. We found a marked rewiring of miRNA-miRNA cooperation between various cancers and revealed conserved and rewired network miRNA hubs. We further identified the common hubs, cancer-specific hubs and other hubs, which tend to target known anticancer drug targets. Finally, miRNA cooperative modules were found to be associated with patient survival in several cancer types. Our study highlights the potential of pan-cancer miRNA-miRNA cooperative regulation as a novel paradigm that may aid in the discovery of tumorigenesis mechanisms and development of anticancer drugs.