The ceRNA hypothesis
Key components within the competing endogenous RNA (ceRNA) hypotheses are microRNA (miRNA) and miRNA response elements (MRE).
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miRNA in itself is not only capable of binding to MRE but also long-noncoding RNA (lncRNA) and pseudogenes, therefore having the ability to post-transcriptionally influence the activity of RNA.
It is important to highlight that each miRNA has multiple RNA targets and most RNA molecules harbor several MREs and can, therefore, be repressed by numerous miRNAs.
The multiplicity of this effect has led to a hypothesis that different RNAs such as pseudo-targets or legitimate targets compete for a finite number of miRNAs, therefore acting as competing as ceRNA. It has been established that miRNA can not only inhibit the function of mRNA, but mRNA can also affect miRNA inversely so the protein-coding RNA or non-coding RNA have a function by competing with miRNA through an identical mechanism.
The hypothesis provides a basis that there is a network across transcription suggesting that protein-coding genes have a function that does not need to be translated to a protein and so are involved in post-transcriptional regulation at the RNA level.
The development of ceRNA
The conception of ceRNA can be traced back to 2007 where Ebert developed a miRNA inhibitor dubbed a miRNA sponge, acting through a string of single MREs.
Acting through competitive inhibition with specific miRNA can block its interaction with the nature target therefore inhibition the function of endogenous miRNA. This has been further expanded through the pseudo-target hypothesis, which proposed that natural or synthetic targets, such as the miRNA sponge, act as competitive inhibitors of miRNA by suppressing miRNA combined with the true target.
The hypothesis was developed further through the dilution aspect of the hypothesis where numerous mRNA targets of miRNA in which one or several mRNA downregulated would lead to an increase in miRNA and silence another targeted mRNA.
The hypothesis was perfected in 2011 whereby ceRNA was proposed to be endogenous with a variety of targets such as mRNA, pseudogenes, lncRNA. In a ceRNA chain, they perhaps have different MRE and can bind to different miRNA. Lastly, the miRNA can silence various transcripts and form a larger, more complex regulatory network.
ceRNA in prostate cancer
PTEN is a key anti-oncogene, the protein production can suppress tumor growth by targeting the PI3K/ Akt signaling pathway.
PTEN and PTENP1 share the same MRE. In 2010 Poliseno and his team published work establishing the pseudogene transcript PTENP1 can increase the cellular levels of PTEN by binding to miR-19, miR-21, miR-26, and miR-214 and therefore exert a suppressive effect on the proliferation of cancerous cells.
Inversely, when downregulated the expression level of PTENP1, the more miRNA would inhibit PTEN, therefore, facilitating tumor growth. This work has been extended to other pseudogenes such as KRAS1P.
These findings suggest that pseudogene functions mirror those of their cognate genes through ceRNA interplay.
ceRNA in liver cancer
Recent research has revealed that a lncRNA called highly upregulated liver cancer (HULC) has an important role in oncogenic processes.
HULC can act as a natural miRNA sponge inhibiting miR-371, therefore, setting free the restraint it has on camp-dependent-protein-kinase catalytic B (PRKACB), which in turn promotes the PKA signaling pathway. The study elucidates that lncRNA can also work as ceRNA.
Typically, miRNA works through binding to the 3’-UTR of some specific mRNAs, and the 3’-UTR is the center of the ceRNA network.
The hyaluronic acid-binding protein versican has been identified to promote hepatocellular carcinogenesis through the binding of the 3’-UTR of versican mRNA can competitively combine with miR-133a, miR-144 and miR-199a-3p regulating the expression of these targets supporting the metastatic potential an invasion of the hepatocellular-carcinoma cells and inhibition of apoptosis.
Perspectives and potentials
The model of ceRNA has helped to develop a new post-transcription regulation model and explains the relationship between the transcript and cell function. Despite this, the hypothesis has opened a new possibility of studying and functionalizing the non-coding transcriptome.
In this respect, the previously uncharacterized lncRNA as ceRNA counterparts for mRNA is flourishing. It should be highlighted that protein-coding genes producing lncRNAs are often over-represented in cancer association studies, being more than twice as likely to be associated with cancer as opposed to human protein-coding genes.
In spite of this, a better understanding of the molecular conditions in which ceRNA interactions occur is of critical importance to understand post-transcriptional regulation.
These need to be examined in vivo to ascertain whether dysregulation would lead to perturbation of the ceRNA crosstalk in a biological setting.
In conclusion, the study of miRNA and ceRNA networks enables a new area of basic cancer research as well as facilitating the development of novel diagnostic and therapeutic tools.
Such an example could include the silencing of aberrantly expressed miRNAs through anti-sense oligomers and recent advances in targeted delivery to tumor cells have shown early promise in mouse models.
The identification of this novel ceRNAs in human cancer may, therefore, represent promising new therapeutic targets whereby it could target alone or in a network, reducing the oncogenic potential or impair chemotherapeutic resistance.
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- Ebert, M.S., J.R. Neilson, and P.A. Sharp, Nat. Methods, 2007. 4: p. 721–726.
- Poliseno, L., et al., Nature, 2010. 465: p. 1033-1038.
- Wang, J., et al., Nucleic Acids Res., 2010. 38: p. 5366-5383.
- Fang, L., et al., FASEB. J, 2013. 27: p. 907-919.