Abstract
MicroRNAs (miRNAs) inhibit expression of target genes by binding to their RNA transcripts. It has been recently shown that RNA transcripts targeted by the same miRNA could “compete” for the miRNA molecules and thereby indirectly regulate each other. Experimental evidence has suggested that the aberration of such miRNA-mediated interaction between RNAs—called competing endogenous RNA (ceRNA) interaction—can play important roles in tumorigenesis. Given the difficulty of deciphering context-specific miRNA binding, and the existence of various gene regulatory factors such as DNA methylation and copy number alteration, inferring context-specific ceRNA interactions accurately is a computationally challenging task. Here we propose a computational method called Cancerin to identify cancer-associated ceRNA interactions. Cancerin incorporates DNA methylation, copy number alteration, gene and miRNA expression datasets to construct cancer-specific ceRNA networks. We applied Cancerin to three cancer datasets from the Cancer Genome Atlas (TCGA) project. Our results indicated that ceRNAs were enriched with cancer-related genes, and ceRNA modules in the inferred ceRNA networks were involved in cancer-associated biological processes. Using LINCS-L1000 shRNA-mediated gene knockdown experiment in breast cancer cell line to assess accuracy, Cancerin was able to predict expression outcome of ceRNA genes with high accuracy.
Highlights
MicroRNAs are a family of short non-coding RNA molecules involved in post-transcriptional gene regulation
CeRNA interaction is a post-transcriptional gene regulation that involves interactions between RNAs competing for common miRNA regulators
Dysregulation of competing endogenous RNA (ceRNA) interactions have been implicated in multiple diseases including cancer
Summary
MicroRNAs (miRNAs) are a family of short non-coding RNA molecules involved in post-transcriptional gene regulation. MiRNAs attach to Argonaute protein to form RNA-induced silencing complexes (RISCs), which bind to miRNA-response-elements (MREs) located on the 30UTR of messenger RNAs (mRNAs). This binding promotes mRNA degradation or inhibit their translation into proteins [1]. As protein synthesis is impacted by miRNA-mRNA binding, gene regulation by miRNAs plays an important role in a wide range of biological processes such as cell growth, differentiation, and apoptosis [3,4,5]. Aberrant changes in miRNA concentration in cells could lead to dysregulation of tumor suppressors or oncogenic genes, which could trigger cancer development and progression [7]
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