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Biological role and regulation of circular RNA as an emerging biomarker and potential therapeutic target for cancer

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Abstract

Circular RNAs (circRNAs) are a unique family of endogenous RNAs devoid of 3′ poly-A tails and 5′ end caps. These single-stranded circRNAs, found in the cytoplasm, are synthesized via back-splicing mechanisms, merging introns, exons, or both, resulting in covalently closed circular loops. They are profusely expressed across the eukaryotic transcriptome and offer heightened stability against exonuclease RNase R compared to linear RNA counterparts. This review endeavors to provide a comprehensive overview of circRNAs’ characteristics, biogenesis, and mechanisms of action. Furthermore, aimed to shed light on the potential of circRNAs as significant biomarkers in various cancer types. It has been performed an exhaustive literature review, drawing on recent studies and findings related to circRNA characteristics, synthesis, function, evaluation techniques, and their associations with oncogenesis. CircRNAs are intricately associated with tumor progression and development. Their multifaceted roles encompass gene regulation through the sponging of proteins and microRNAs, controlling transcription and splicing, interacting with RNA binding proteins (RBPs), and facilitating gene translation. Due to these varied roles, circRNAs have become a focal point in tumor pathology investigations, given their promising potential as both biomarkers and therapeutic agents. CircRNAs, due to their unique biogenesis and multifunctionality, hold immense promise in the realm of oncology. Their stability, widespread expression, and intricate involvement in gene regulation underscore their prospective utility as reliable biomarkers and therapeutic targets in cancer. As our understanding of circRNAs deepens, advanced techniques for their detection, evaluation, and manipulation will likely emerge. These advancements might catalyze the translation of circRNA-based diagnostics and therapeutics into clinical practice, potentially revolutionizing cancer care and prognosis.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

ANKRD52:

Ankyrin repeat domain 52

BWA-MEM:

Burrow-wheeler aligner’s maximal exact match

CDR1as:

Cerebellar degeneration-related protein 1 antisense

ceRNA:

Competitive endogenous RNA

CDK2:

Cyclin-dependent kinase 2

circRNA:

Circular RNA

circ-Foxo3:

Circular RNA forkhead box O3

circHIPK3:

Circular RNA homeodomain-interacting protein kinase 3

circ-MBL:

Circular muscleblind

circMTO1:

Circular RNA mitochondrial tRNA translation optimization 1

circ-ZNF609:

Circular RNA zinc finger protein 609

CIRI:

Circular RNA identifier

CSCD:

Cancer-specific circRNA database

EIciRNAs:

Exon–intron circRNAs

IRES:

Internal ribosome entry site

KNIFE:

Known and novel isoform explorer

MREs:

MiRNA response elements

miRNA:

MicroRNA

ncRNAs:

Non-coding RNA

NCLScan:

Non-co-linear transcripts scan

PTESFinder:

Post-transcriptional exon shuffling finder

RBPs:

RNA binding proteins

RPAD:

RNase R protocol accompanied by poly (A) + RNA depletion and polyadenylation

TDP-43:

TAR DNA-binding protein 43

TSCD:

Tissue-specific CircRNA database

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Acknowledgements

The authors would like to express their gratitude to Dr. Irina Zamfir, MD, RCP London, Basildon University Hospital UK, for providing professional English editing of this manuscript and for editorial support.

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  1. Institute of Molecular Biology and Biotechnology, The University of Lahore, Lahore, Pakistan

    Ayman Saleem, Muhammad Umer Khan, Tazeen Zahid & Inam Ullah

  2. Centre for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan

    Iqra Khurram, Muhammad Usman Ghani & Rakhtasha Munir

  3. Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania

    Daniela Calina

  4. Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador

    Javad Sharifi-Rad

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Saleem, A., Khan, M.U., Zahid, T. et al. Biological role and regulation of circular RNA as an emerging biomarker and potential therapeutic target for cancer. Mol Biol Rep 51, 296 (2024). https://doi.org/10.1007/s11033-024-09211-3

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