ceRNA cross-talk in cancer: when ce-bling rivalries go awry

Abstract

The cancer transcriptome is characterized by aberrant expression of both protein-coding and noncoding transcripts. Similar to mRNAs, a significant portion of the noncoding transcriptome, including long noncoding RNAs and pseudogenes, harbors microRNA (miRNA)-response elements (MRE). The recent discovery of competitive endogenous RNAs (ceRNA), natural decoys that compete for a common pool of miRNAs, provides a framework to systematically functionalize MRE-harboring noncoding RNAs and integrate them with the protein-coding RNA dimension in complex ceRNA networks. Functional interactions in ceRNA networks aid in coordinating a number of biologic processes and, when perturbed, contribute to disease pathogenesis. In this review, we discuss recent discoveries that implicate natural miRNA decoys in the development of cancer.

Significance: Cross-talk between ceRNAs through shared miRNAs represents a novel layer of gene regulation that plays important roles in the physiology and development of diseases such as cancer. As cross-talk can be predicted on the basis of the overlap of miRNA-binding sites, we are now one step closer to a complete functionalization of the human transcriptome, especially the noncoding space.

Figure 1

The ceRNA concept. (A) The schema outlines the concept of ceRNAs. Two transcripts, ceRNA1 in orange and ceRNA2 in green, have two different MREs (blue and red boxes, complementary to miRNAs miR1 and miR2, respectively) in common. Thus, miR1 and miR2 repress both ceRNAs. When miR1 and miR2 target ceRNA1 and are therefore eliminated from the pool of available miRNA, ceRNA1 effectively inhibits the repressive activity of miR1 and miR2 towards ceRNA2 (dashed inhibition arrow). As ceRNA crosstalk is, in theory, reciprocal, binding of miR1 and miR2 to ceRNA2 inhibits their activity towards ceRNA1. (B) Changing the abundance of one ceRNA will lead to a similar effect in the levels of the other ceRNA, i.e. upregulation of ceRNA1 will lead to increased levels of ceRNA2. (C) Deregulation of one ceRNA results in changes in the pool of available, unbound ceRNAs and miRNAs (adapted from reference 33). Increased expression of ceRNA1 will first lead to a decrease in unbound miRNA molecules. Once the majority of miRNA molecules are bound, the levels of unbound, unrepressed ceRNA1 and ceRNA2 can increase.

Figure 2

3′UTRs as ceRNAs. (A) Independently expressed 3′UTRs can arise through various mechanisms. (i) 3′UTRs are typically associated with the CDSs of their genes, but they nevertheless could serve as ceRNAs for other transcripts. (ii) Alternative promoters may drive independent expression of 3′UTRs. (iii) Posttranscriptional cleavage of transcripts may dissociate the CDS from its 3′UTR. (iv) Genomic translocations resulting in fusion genes may place 3′UTRs under the control of foreign promoters. (v) Transcriptional read-through of two adjacent genes could result in chimeric transcripts and abnormal levels of the downstream transcript. (vi) Aberrant trans-splicing could join two unlinked transcripts, also resulting in chimeric transcripts. (B) Independently expressed 3′UTRs can either serve as miRNA sponges to de-repress expression of their CDS-associated counterparts, or other transcripts with which they share MREs.

Figure 3

ceRNA networks. (A) Example of a ceRNETs. The schematic depicts a ceRNET with a moderate degree of complexity that contains several indirect interactions (outlined by ‘glowing’ connections). The nodes highlighted in red could represent critical nodes that are connected to numerous other ceRNAs and thus may have the most impact on the network when deregulated. (B) Intertwined transcriptional and ceRNA networks. A transcription factor may act as ceRNA via its mRNA transcript, while its protein stimulates transcription of targets that in turn also decoy miRNAs. (C) Indirect interactions amplify ceRNA crosstalk. These two networks consisting of three ceRNAs differ only by a miRNA connection between ceRNA2 and ceRNA3. When this connection is lacking, ceRNA1 (shown in green) has only direct effects on ceRNAs 2 and 3 (top panel). If the connection between ceRNAs 2 and 3 is present, then increasing the abundance of ceRNA1 will have direct effects as well as indirect effects (bottom panel). In the latter case, elevated levels of ceRNA1 will increase ceRNA2, which in turn will increase ceRNA3. Moreover, ceRNA1 will affect ceRNA3, which will then impact ceRNA2 and thus ceRNAs2 and 3 are doubly regulated through ceRNA crosstalk.