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High-throughput validation of ceRNA regulatory networks

Background: MicroRNAs (miRNAs) play multiple roles in tumor biology [1]. Interestingly, reports from multiple groups suggest that miRNA targets may be coupled through competitive stoichiometric sequestration [2]. Specifically, computational models predicted [3, 4] and experimental assays confirmed [5, 6] that miRNA activity is dependent on miRNA target abundance, and consequently, changes to the abundance of some miRNA targets lead to changes to the regulation and abundance of their other targets. The resulting indirect regulatory influence between miRNA targets resembles competition and has been dubbed competitive endogenous RNA (ceRNA) [5, 7, 8]. Recent studies have questioned the physiological relevance of ceRNA interactions [9], researchers ability to accurately predict these interactions [10], and the number of genes that are impacted by ceRNA interactions in specific cellular contexts [11]. Results: To address these concerns, we reverse engineered ceRNA networks (ceRNETs) in breast and prostate adenocarcinomas using context-specific TCGA profiles [12-14], and tested whether ceRNA interactions can predict the effects of RNAi-mediated gene silencing perturbations in PC3 and MCF7 cells. Our results, based on tests of thousands of inferred ceRNA interactions that are predicted to alter hundreds of cancer genes in each of the two tumor contexts, confirmed statistically significant effects for half of the predicted targets. Conclusions: Our results suggest that the expression of a significant fraction of cancer genes may be regulated by ceRNA interactions in each of the two tumor contexts.

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