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Review
. 2023 Sep;42(38):2783-2800.
doi: 10.1038/s41388-023-02780-w. Epub 2023 Aug 16.

Going circular: history, present, and future of circRNAs in cancer

Giuseppina Pisignano  1 , David C Michael  2 , Tanvi H Visal  3   4 , Radu Pirlog  3   4 , Michael Ladomery  5 , George A Calin  6   7
Affiliations
Review

Going circular: history, present, and future of circRNAs in cancer

Giuseppina Pisignano et al. Oncogene. 2023 Sep.

Abstract

To date, thousands of highly abundant and conserved single-stranded RNA molecules shaped into ring structures (circRNAs) have been identified. CircRNAs are multifunctional molecules that have been shown to regulate gene expression transcriptionally and post-transcriptionally and exhibit distinct tissue- and development-specific expression patterns associated with a variety of normal and disease conditions, including cancer pathogenesis. Over the past years, due to their intrinsic stability and resistance to ribonucleases, particular attention has been drawn to their use as reliable diagnostic and prognostic biomarkers in cancer diagnosis, treatment, and prevention. However, there are some critical caveats to their utility in the clinic. Their circular shape limits their annotation and a complete functional elucidation is lacking. This makes their detection and biomedical application still challenging. Herein, we review the current knowledge of circRNA biogenesis and function, and of their involvement in tumorigenesis and potential utility in cancer-targeted therapy.

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Conflict of interest statement

GAC is one of the scientific founders of Ithax Pharmaceuticals, Inc. No conflict of interest to declare for the other authors.

Figures

Fig. 1
Fig. 1. The discovery of circRNAs.
Timeline of milestone events leading to the discovery, research and development of circRNAs.
Fig. 2
Fig. 2. Canonical splicing vs back-splicing.
Starting from the same pre-mRNA molecule, linear splicing (red arrows) and head-to-tail back-splicing (blue arrows) lead to a differential outcome in either processed mRNA/lncRNAs molecules or several types of circRNAs, respectively. Adapted from “RNA Processing in Eukaryotes 2”, by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates.
Fig. 3
Fig. 3. Mechanisms leading to the biogenesis of circRNAs.
Three main mechanisms of back-splicing, such as lariat-driven circularization (exon skipping) (A), intron pairing-driven circularization (B), and RNA binding protein (RBP)‐driven circularization (C) lead to the biogenesis of circRNAs. Alternative processes (D) can also lead to the biogenesis of other special classes of circRNAs, including intergenic circRNAs or rt-circRNAs and f-circRNAs, which are frequently associated with pathological conditions. Created with BioRender.com.
Fig. 4
Fig. 4. Biological functions of circRNAs.
CircRNAs can work as multifunctional devices serving as transcription regulators of their parental genes (1), as microRNA sponges affecting genes post-transcriptionally (2), or as translated short peptides/proteins (3). Additionally, circRNAs can affect the stability of other RNA molecules (mRNAs or lncRNAs) (4), accumulate inside of exosomes and mediate cellular response (5), engage with RBPs and acting as either decoy (6), or scaffold molecules (7), as well as directing RBP cellular localization (8). Adapted from “DNA vs mRNA Transfection”, by BioRender.com (2022). Retrieved from https://app.biorender.com/biorender-templates.
Fig. 5
Fig. 5. CircRNAs as biomarkers and therapeutic targets in human cancer.
An up-to-date summary of circRNAs that show promise as clinical biomarkers (outmost circle) and/or as therapeutic targets (syringe icons pointing towards the chart), associated with different types of cancer. Created with BioRender.com.
See this image and copyright information in PMC

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