Circular RNAs in cancer development - Peter Zaphiropoulos
Circular RNAs in eukaryotes were discovered more than twenty years ago, with our Department pioneering in these early studies (PNAS, 93:6536-41). Initially, RNA circles were thought of as rare by-products of the splicing machinery. However, the advent of next generation sequencing has provided compelling evidence that circular RNAs can be quite abundant, in fact more abundant than the mRNAs originating from the same gene.
Additionally, an increasing body of evidence has linked circular RNA expression with human biology, including brain function and cancer development. Our current research efforts centre on the impact of RNA circles in the biology of the most common paediatric cancer in the brain, medulloblastoma.
Mechanism of circular RNA biogenesis
RNA circles are produced via a back-splicing mechanism, where the 3´ end of an exon is spliced to the 5´ end of an upstream exon. This can be facilitated by inverted repeats in the introns that flank the back-spliced exons, as highlighted in the diagram.
Function of circular RNA
RNA circles are mostly known to act as molecular traps for microRNAs. This is in-line with their increased stability, which relates to the inability of exonucleases to attack a circular species. Additionally, emerging evidence is linking circular RNAs with protein interactions and with the capacity to encode peptides via internal ribosome entry sites.
Circular RNAs and cancer
There is convincing evidence that circular RNA expression is de-regulated in cancer. Moreover, in colorectal, hepatic, prostate and bladder cancer, the de-regulated circular RNAs have been demonstrated to act as oncogenes/tumour suppressor genes by sponging tumour suppressor/oncogenic microRNAs.
However, little is known on how circular RNAs impact medulloblastoma development. To fill this gap, RNA-sequencing approaches that can detect back-spliced junctions, the marker of RNA circles, are implemented in a large collection of human cerebellar and medulloblastoma samples. It is hypothesised that differentially expressed circular RNAs in normal versus cancerous tissue may not simply be “passenger molecules” but actually functionally impact disease development, and we aim to provide clarity in this direction.
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- Azatyan, A., Zhang, S., Darabi, A., Siesjö, P., Wang, T., and Zaphiropoulos, P.G. (2021) `Circular RNAs in Hedgehog Signaling Activation and Hedgehog-Mediated Medulloblastoma Tumors.' Cancers 13(20):5138; doi: 10.3390/cancers13205138.
- Azatyan, A., Gallo, G., Diao, Y., Selivanova, G., Johnsen, J.I., and Zaphiropoulos, P.G. (2019) ‘RITA downregulates Hedgehog-GLI in medulloblastoma and rhabdomyosarcoma cells via JNK-dependent but p53-independent mechanism.’ Cancer Letters 442, 341-350; doi: 10.1016/j.canlet. 2018.11.005.
- Zaphiropoulos P.G. (2018) ‘Circles in action, circles in function.’ AME Medical Journal 3, 81; doi:10.21037/amj.2018.07.08.
- Diao, Y., Rahman, M.F-U., Vyatkin, Y., Azatyan, A., St Laurent, G., Kapranov, P., and Zaphiropoulos, P.G. (2018) ‘Identification of GLI1 target genes and regulatory circuits in human cancer cells.’ Mol. Oncology 12, 1718-1734; doi:10.1002/1878-0261.12366