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

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.

Knockdown of circSMAD2 inhibits the tumorigenesis of gallbladder cancer through binding with eIF4A3

“…RBPs are required for modulation of the circRNA biogenesis in a positive or negative way [ 18 , 19 ]. In this research, our data showed that circSMAD2 could bind with eIF4A3.…”

Circular RNA hsa_circ_0001874 is an indicator for gastric cancer

“…However, accumulating evidences have suggested that some circRNAs are aberrantly expressed and related to multiple pathological processes of gastric carcinogenesis, including tumorigenesis, development, and metastasis 4,11 . As crucial regulators, circRNAs have been found to exert their biological functions mainly acting as miRNA sponges 12 . Wang et al 13 illustrated that the downregulated circ‐ITCH expression in GC promoted proliferation, migration, invasion, and epithelial‐mesenchymal transition (EMT) via a miR‐199a‐5p sponge mechanism.…”

“… 4 , 11 As crucial regulators, circRNAs have been found to exert their biological functions mainly acting as miRNA sponges. 12 Wang et al 13 illustrated that the downregulated circ‐ITCH expression in GC promoted proliferation, migration, invasion, and epithelial‐mesenchymal transition (EMT) via a miR‐199a‐5p sponge mechanism. Zhang et al 14 showed that upregulated circRNA_0005529 expression facilitates GC growth and metastasis by regulating the miR‐527/Sp1 axis.…”

New Molecular Mechanisms and Clinical Impact of circRNAs in Human Cancer

“…Circular RNAs (circRNAs) were first detected by electron microscopy nearly 45 years ago and later confirmed to be present in the cytoplasm of eukaryotic cells [3,4]. Interestingly, through new RNA sequencing methodologies and new bioinformatics approaches, circRNAs have forcefully emerged in the clinical and basic research landscape [1,5,6]. These technologies highlighted that human transcriptome counts more than 180,000 circRNAs [7] and that their expression Figure 1.…”

“…Diverse biological functions of circRNAs have been reported. In the scientific literature, the most reported function is that in which the circRNAs act as "sponges" for miRNAs, lncRNAs and some mRNAs, affecting the functions of their target genes [5,9]. This review aims to discuss other circRNA functions that are emerging.…”