Insights Into the Role of CircRNAs: Biogenesis, Characterization, Functional, and Clinical Impact in Human Malignancies.

Sabah Nisar,Davide Bedognetti,Gyan Chand,Farrukh Jamal,Mohammad Haris,Ikhlak Ahmed,Thasni Karedath,Wael El-Rifai,Sheema Hashem,Michael P Frenneaux,Mayank Singh,Puneet Bagga,Shahab Uddin,Ajaz A Bhat,Arshi Rizwan,Ravinder Reddy,Muzafar A Macha

doi:10.3389/fcell.2021.617281

Abstract

Circular RNAs (circRNAs) are an evolutionarily conserved novel class of non-coding endogenous RNAs (ncRNAs) found in the eukaryotic transcriptome, originally believed to be aberrant RNA splicing by-products with decreased functionality. However, recent advances in high-throughput genomic technology have allowed circRNAs to be characterized in detail and revealed their role in controlling various biological and molecular processes, the most essential being gene regulation. Because of the structural stability, high expression, availability of microRNA (miRNA) binding sites and tissue-specific expression, circRNAs have become hot topic of research in RNA biology. Compared to the linear RNA, circRNAs are produced differentially by backsplicing exons or lariat introns from a pre-messenger RNA (mRNA) forming a covalently closed loop structure missing 3′ poly-(A) tail or 5′ cap, rendering them immune to exonuclease-mediated degradation. Emerging research has identified multifaceted roles of circRNAs as miRNA and RNA binding protein (RBP) sponges and transcription, translation, and splicing event regulators. CircRNAs have been involved in many human illnesses, including cancer and neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, due to their aberrant expression in different pathological conditions. The functional versatility exhibited by circRNAs enables them to serve as potential diagnostic or predictive biomarkers for various diseases. This review discusses the properties, characterization, profiling, and the diverse molecular mechanisms of circRNAs and their use as potential therapeutic targets in different human malignancies.

Highlights

Circular RNAs are single-stranded non-coding RNAs that are covalently linked to form a continuous closed-loop and participate in the regulation of transcriptional and posttranscriptional gene expression (Wang M. et al, 2017)
Epigenetic modifications within the histones and gene bodies affect alternative splicing and directly impact circRNA biogenesis (Shukla et al, 2011; Bentley, 2014). These findings suggest that even though the biogenesis of circRNA is a product of inefficient canonical splicing, the introns within the circRNAs mostly spliced out during the process indicates biogenesis is instead a straightforward regulatory process orchestrated in the splicing machinery (Westholm et al, 2014)
CircPTK2 was found to function as a sponge of miR-429/miR-200b-3p, and miR-429/miR-200b-3p and influenced their downstream targets (Wang L. et al, 2018). Another circRNA, circPRMT5 was found to be highly expressed in non-small cell lung cancer (NSCLC) tissues and cell lines and positively correlated with large tumor size, advanced clinical stage, lymph node metastasis as well as poor prognosis (Wang Y. et al, 2019)

Summary

Introduction

Circular RNAs (circRNAs) are single-stranded non-coding RNAs that are covalently linked to form a continuous closed-loop and participate in the regulation of transcriptional and posttranscriptional gene expression (Wang M. et al, 2017). Another study showed the upregulation of circRNA hsa-circ-0020397 and the downregulation of miR-138 in CRC cells (Zhang X.L. et al, 2017).

Results

Conclusion