Over the past decade, circular RNAs (circRNAs) have emerged as a large class of primarily non-coding RNA molecules, many of which have key roles in cancer development and progression through diverse mechanisms of action. CircRNAs often have tissue-restricted and cancer-specific expression patterns, and accumulating data suggest that these molecules are of potential clinical relevance and utility. In particular, circRNAs have strong potential as diagnostic, prognostic and predictive biomarkers, which is underscored by their detectability in liquid biopsy samples such as in plasma, saliva and urine. However, technical issues in the detection and assessment of circRNAs as well as biological knowledge gaps need to be addressed to move this relatively young field of research forward and bring circRNAs to the forefront of clinical practice. Herein, we review the current knowledge regarding circRNA biogenesis, regulation and functions in cancer as well as their clinical potential as biomarkers, therapeutic agents and drug targets.
Human cells produce many more unique circular RNAs (circRNAs) than we have protein-coding genes; some of these circRNAs are highly abundant, conserved and have important physiological and/or pathophysiological roles.
Most circRNAs are derived from protein-coding genes, are produced by back-splicing events carried out by the canonical splicing machinery and show tissue-specific expression patterns.
CircRNAs are highly stable molecules that are mostly present in the cytosol, where they can function through interactions with other molecules, including proteins and microRNAs.
Deciphering the mechanisms of action of circRNAs can be challenging and the field of circRNA research is associated with several controversies.
CircRNAs are promising as biomarkers for cancer diagnosis and prognostication as well as for early cancer detection and as therapeutic targets or agents to inhibit oncogenic microRNAs or proteins.
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The work of the authors is supported by a grant to L.S.K. from the Lundbeck Foundation (R307-2018-3433) and to J.K. from the Danish Cancer Society (R269-A15768). We thank M. Jarlstad Olesen, S. Seeler and A. Færch Nielsen for a careful and critical reading of the manuscript.
The authors declare no competing interests.
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Nature Reviews Clinical Oncology thanks S.-Y. Cheng, S. Huang and B. B. Yang for their contribution to the peer review of this work.
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Kristensen, L.S., Jakobsen, T., Hager, H. et al. The emerging roles of circRNAs in cancer and oncology. Nat Rev Clin Oncol 19, 188–206 (2022). https://doi.org/10.1038/s41571-021-00585-y
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