A Method for Constructing an Integrative Network of Competing Endogenous RNAs

Since the new gene regulation involving competing endogenous RNA (ceRNA) interactions targeted by common microRNAs (miRNAs) was found, several computational methods have been proposed to derive ceRNA networks. However, most of the ceRNA networks are restricted to represent either miRNA-target RNA interactions or lncRNA-miRNA-mRNA interactions. From the extensive data analysis, we found that competition for miRNA-binding occurs not only between lncRNAs and mRNAs but also between lncRNAs or between mRNAs. Furthermore, a large number of pseudogenes also act as ceRNAs, thereby regulate other genes. In this study, we considered all lncRNAs, mRNAs and pseudogenes as potential ceRNAs and developed a method for constructing an integrative ceRNA network which includes all possible interactions of ceRNAs mediated by miRNAs: lncRNA-miRNA-mRNA, lncRNA-miRNA-lncRNA, lncRNA-miRNA-pseudogene, mRNA-miRNA-mRNA, mRNA-miRNA-pseudogene, and pseudogene-miRNA-pseudogene. We constructed integrative ceRNA networks for breast cancer, liver cancer and lung cancer, and derived several triplets of ceRNAs which can be used as potential prognostic biomarkers. The potential prognostic triplets could not be found when only lncRNA-miRNA-mRNA interactions were considered. Although preliminary, our approach to constructing integrative ceRNA networks is applicable to multiple types of cancer and will help us find potential prognostic biomarkers in cancer.