If you have been following our blog posts about microRNA (miRNA) – or if you have been studying the microRNA world – you are likely familiar with the small 22-nucleotide RNAs that target messenger RNAs (mRNAs) to repress their translation into protein.
The ceRNA hypothesis
In 2011, Pier Paolo Pandolfi research lab proposed the hypothesis that different types of RNA molecules compete for microRNA binding and reduce the repressive effects of microRNAs on their mRNA targets (1).
In other words, when there are no competing transcripts present, microRNAs can affect translational repression or can enhance the degradation of mRNAs. When competitive endogenous RNAs (ceRNAs) are upregulated, ceRNAs compete to bind the shared microRNA, inducing increases in mRNA translation (2).
Competitive endogenous RNA may include various types of RNA transcripts – such as circular RNA (circRNA), long noncoding RNA (lncRNA), pseudogene and protein-coding mRNA.
Ever since its initial proposal, the Pier Paolo Pandolfi research lab’s hypothesis has gained substantial attention. This hypothesis has not been immune to controversy, however. In an article recently published in Nature Review Genetics, Thomson and Dinger thoroughly evaluated the evidence for and against the ceRNA hypothesis to assess the impact of endogenous miRNA-sponge interactions (3). Read more in the review here.
The ceRNA roles in cancer pathogenesis
In other studies, ceRNA has been demonstrated to play significant roles in cancer pathogenesis by modulating the expression of key tumorigenic or tumor suppressor genes.
Dai, Li, Zhou and Liang reviewed recent studies that indicate ceRNA plays a role in the progression of cancer (4). For instance, protein-coding RNAs, lncRNAs and pseudogene transcripts can all function as ceRNAs and contribute to inducing uncontrolled proliferation.
CDC42 is a gene involved in cell cycle progression – inhibiting proliferation, colony formation and tumor growth following enhanced translation. The study showed that CD44 mRNA competes with CDC42 mRNA for miRNA binding. The increase of CD44 mRNA frees the CDC42 mRNA target from repression and leads to favorable results in epithelial ovarian cancer.
The loss of CD44 expression could potentially induce tumorigenesis. Similarly, HMGA2 promotes lung tumor formation by competing with the TGF-β co-receptor TGFβR3 for let-7 occupancy – which activates TGF-β signaling involved in lung cancer progression.
Additionally, ceRNAs have also been identified in the inhibition of cellular growth and proliferation. For instance, the pseudogene PTENP1 competes with PTEN for miRNA binding, modulating the derepression of specific miRNA targets. Loss of PTENP1 increases PTEN-miRNA binding and decreases PTEN translation – leading to reduced tumor suppressor functions. Read more interesting examples here.
Though it remains in its infancy, ceRNA has emerged as a novel field of RNA biology and has been contributing to the development of miRNA-based therapeutics.
For miRNA profiling, the miScript PCR System offers a suite of specialized products designed to overcome common challenges associated with circulating miRNA quantification. Similarly, the human RT² lncRNA PCR Arrays offer a leading solution for circulating lncRNA quantification.
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The applications presented here are for research use only. Not for use in diagnostic procedures.
- 1. 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 146,353–8. (Link)
- 2. de Giorgio, A., Krell, J., Harding, V., Stebbing, J. and Castellano, L. (2013) Emerging roles of competing endogenous RNAs in cancer: insights from the regulation of PTEN. Mol Cell Biol. 33, 3976–3982. (Link)
- 3. Thomson, D.W. and Dinger, M.E. (2016) Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet. 17, 272–83. (Link)
- 4. Dai, Q., Li, J., Zhou, K. and Liang, T. (2015) Competing endogenous RNA: A novel posttranscriptional regulatory dimension associated with the progression of cancer. Oncol Lett. 10, 2683–2690. (Link)