Competing endogenous RNA (CeRNA)

Competing endogenous RNAs (abbreviated ceRNAs) communicate with and regulate other RNA transcripts by competing for shared microRNAs.^[1]

Mechanism of action

The ceRNA hypothesis stems from the observation that RNA transcripts can communicate with each other through a recently discovered mechanism.^[2] MicroRNAs are tiny snippets of RNA (~22nt long) which negatively regulate target gene expression via translational inhibition or transcript cleavage. A microRNA may target many different transcripts, and conversely, individual transcripts may be bound by multiple different microRNAs. In addition to this conventional microRNA → RNA function, it has recently been established that a reversed RNA → microRNA dimension exists, whereby ceRNAs regulate transcript expression via competition for common microRNAs, with microRNA response elements (abbreviated MREs) as the building blocks of this ‘RNA language’.^[1] RNA transcripts, both protein-coding and non-coding, thus have the ability to compete for microRNA binding and co-regulate each other in complex ceRNA networks. The ceRNA language represents an added trans-regulatory dimension to mRNA biology besides the protein-coding function. Of critical importance, this new language allows the prediction and identification of ceRNAs for a given mRNA, as well as to define ceRNA networks. In turn, this enables the functionalization of the transcriptome irrespective of whether the transcripts encode for protein.

On the basis of this new theory, expressed pseudogenes transcribed from genomic loci that closely resemble their ancestral gene but generally do not encode functional proteins, become putative ideal ceRNAs for their ancestral genes in view of their homology. This attributes a function to pseudogenes, which have thus been perceived as ‘evolutionary relics’ or ‘junk’.^[2]

The PTEN ceRNA network

PTEN is a critical tumor suppressor gene which is frequently altered in multiple human cancers and is a negative regulator of the oncogenic Phosphoinositide 3-kinase/Akt signaling pathway. Three recent studies have identified and successfully validated protein-coding transcripts as PTEN ceRNAs in prostate cancer,^[3] glioblastoma^[4] and melanoma.^[5] PTEN ceRNAs CNOT6L, VAPA and ZEB2 have been shown to regulate PTEN expression, PI3K signaling, and cell proliferation in a 3’UTR- and microRNA-dependent manner.^[3][5] Similarly, in glioblastoma, siRNA-mediated silencing of 13 predicted PTEN ceRNAs including Retinoblastoma protein (RB1), RUNX1 and VEGFA downregulated PTEN expression in a 3’UTR-dependent manner and increased tumor cell growth.^[4]

Additionally, PTEN’s non protein-coding pseudogene, PTENP1, is able to affect PTEN expression, downstream PI3K signaling and cell proliferation by directly competing for PTEN-targeting microRNAs.^[2]

Other validated ceRNA regulators

KRAS1P

Another pseudogene shown to have ceRNA activity is that of the proto-oncogene KRAS, KRAS1P, which increases KRAS transcript abundance and accelerates cell growth.^[2]

Versican

The versican 3’UTR has been shown to regulate expression of the matrix protein fibronectin via antagonizing miR-199a function.^[6]

Linc-MD1

Linc-MD1, a muscle-specific long non-coding RNA, activates muscle-specific gene expression by regulating expression of MAML1 and MEF2C via antagonizing miR-133 and miR-135.^[7]

HSUR 1, 2

T cells transformed by the primate virus Herpesvirus saimiri (HVS) have been shown to express viral U-rich noncoding RNAs called HSURs. Several of these HSURs are able to bind to and compete for three host-cell microRNAs and thus regulate host-cell gene expression.^[8]

Highly Up-regulated in Liver Cancer (HULC)

HULC is one of the most upregulated of all genes in hepatocellular carcinoma. CREB (cAMP response element binding protein) has been implicated in the upregulation of HULC.^[9] HULC RNA inhibits miR-372 activity through a ceRNA function, leading to derepression of one of its target genes, PRKACB, which can then induce the phosphorylation and activation of CREB. Overall, HULC lncRNA is part of a self-amplifying autoregulatory loop in which it sponges miR-372 to activate CREB, and in turn upregulates its own levels.

See also

• Gene expression
• Epigenetics
• MicroRNA
• Tumor suppressor gene
• PTEN

References

1. ^ ^{a b} Salmena, L., Poliseno, L., Tay, Y., Kats, L. and Pandolfi, P.P. (2011). A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 146, 353-358.
2. ^ ^{a b c d} Poliseno, L., Salmena, L., Zhang, J., Carver, B., Haveman, W.J., and Pandolfi, P.P. (2010). A coding-independent function of gene and pseudogene mRNAs regulates tumour biology. Nature 465, 1033-1038.
3. ^ ^{a b} Tay, Y., Kats, L., Salmena, L., Weiss, D., Tan, S.M., Ala, U., Karreth, F., Poliseno, L., Provero, P., Di Cunto, F., et al. (2011). Coding-independent regulation of the tumor suppressor PTEN by competing endogenous mRNAs. Cell 147, 344–357.
4. ^ ^{a b} Sumazin, P., Yang, X., Chiu, H.-S., Chung, W.-J., Iyer, A., Llobet-Navas, D., Rajbhandari, P., Bansal, M., Guarnieri, P., Silva, J., et al. (2011). An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma. Cell 147, 370–381.
5. ^ ^{a b} Karreth, F.A., Tay, Y., Perna, D., Ala, U., Tan, S.M., Rust, A.G., DeNicola, G., Webster, K.A., Weiss, D., Perez-Mancera, P.A., et al. (2011). In vivo identification of tumor-suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell 147, 382–395.
6. ^ Lee, D.Y., Jeyapalan, Z., Fang, L., Yang, J., Zhang, Y., Yee, A.Y., Li, M., Du, W.W., Shatseva, T., and Yang, B.B. (2010). Expression of versican 3’-untranslated region modulates endogenous microRNA functions. PLoS One 5, e13599.
7. ^ Cesana, M., Cacchiarelli, D., Legnini, I., Santini, T., Sthandier, O., Chinappi, M., Tramontano, A., and Bozzoni, I. (2011). A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147, 358–369.
8. ^ Cazalla, D., Yario, T., and Steitz, J.A. (2010) Down-regulation of a host microRNA by a Herpesvirus saimiri noncoding RNA. Science 328, 1563-1566.
9. ^ Wang, J., Liu, X., Wu, H., Ni, P., Gu, Z., Qiao, Y., Chen, N., Sun, F., and Fan, Q. (2010) CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer. Nucleic Acids Res 38, 5366-5383.

External links

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