Abstract
BackgroundIn addition to direct targeting and repressing mRNAs, recent studies reported that microRNAs (miRNAs) can bridge up an alternative layer of post-transcriptional gene regulatory networks. The competing endogenous RNA (ceRNA) regulation depicts the scenario where pairs of genes (ceRNAs) sharing, fully or partially, common binding miRNAs (miRNA program) can establish coexpression through competition for a limited pool of the miRNA program. While the dynamics of ceRNA regulation among cellular conditions have been verified based on in silico and in vitro experiments, comprehensive investigation into the strength of ceRNA regulation in human datasets remains largely unexplored. Furthermore, pan-cancer analysis of ceRNA regulation, to our knowledge, has not been systematically investigated.ResultsIn the present study we explored optimal conditions for ceRNA regulation, investigated functions governed by ceRNA regulation, and evaluated pan-cancer effects. We started by investigating how essential factors, such as the size of miRNA programs, the number of miRNA program binding sites, and expression levels of miRNA programs and ceRNAs affect the ceRNA regulation capacity in tumors derived from glioblastoma multiforme patients captured by The Cancer Genome Atlas (TCGA). We demonstrated that increased numbers of common targeting miRNAs as well as the abundance of binding sites enhance ceRNA regulation and strengthen coexpression of ceRNA pairs. Also, our investigation revealed that the strength of ceRNA regulation is dependent on expression levels of both miRNA programs and ceRNAs. Through functional annotation analysis, our results indicated that ceRNA regulation is highly associated with essential cellular functions and diseases including cancer. Furthermore, the highly intertwined ceRNA regulatory relationship enables constitutive and effective intra-function regulation of genes in diverse types of cancer.ConclusionsUsing gene and microRNA expression datasets from TCGA, we successfully quantified the optimal conditions for ceRNA regulation, which hinge on four essential parameters of ceRNAs. Our analysis suggests optimized ceRNA regulation is related to disease pathways and essential cellular functions. Furthermore, although the strength of ceRNA regulation is dynamic among cancers, its governing functions are stably maintained. The findings of this report contribute to better understanding of ceRNA dynamics and its crucial roles in cancers.
Highlights
In addition to direct targeting and repressing mRNAs, recent studies reported that microRNAs can bridge up an alternative layer of post-transcriptional gene regulatory networks
We started by investigating how essential factors, such as the size of miRNA programs, the number of miRNA program binding sites, and expression levels of miRNA programs and competing endogenous RNA (ceRNA) affect the ceRNA regulation in tumor samples from glioblastoma multiforme (GBM) patients
We performed the goodness-of-fit tests (Kolmogorov-Smirnov test; K-S test) among the cumulative distribution functions (CDFs) to pinpoint whether or not the optimal conditions for intensified ceRNA regulation depend on the essential factors (Figure 1B)
Summary
In addition to direct targeting and repressing mRNAs, recent studies reported that microRNAs (miRNAs) can bridge up an alternative layer of post-transcriptional gene regulatory networks. A group of short single-stranded RNAs, namely microRNAs (miRNAs), has been widely investigated in this decade. With an average length of 22 nucleotides only, miRNAs are not protein coding transcripts. Instead, they fulfill the role of regulators of gene expression by complementarily binding to 3’ untranslated regions (3’ UTRs) of target mRNA transcripts [1,2]. According to existing biological evidence, the binding of miRNAs on mRNA can cause mRNA degradation or suppression of translation, and may affect expression of up to one third of the protein coding genes in humans [2]. With advances in next-generation sequencing, a great number of novel miRNAs have been identified and deposited in the public database miRBase [8], increasing the complexity of miRNA regulation
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