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Circular RNAs (circRNAs) are a novel class of endogenous noncoding RNAs, which is a field of much research interest and activity. Unlike linear RNAs, such as mRNAs, miRNAs and lncRNAs, with a 5' cap and 3' tail structure, circRNAs are characterized by a covalently closed loop structure formed by the back-splicing event. Currently, circRNAs have become the most interesting molecules due to their high abundance, stability, and conservation in mammalian cells. It has been reported that circRNAs orchestrate gene expression by acting as miRNAs sponges, interacting with RNA binding proteins (RBPs) and regulating transcription.
CircRNA is highly expressed, with reported increased abundance compared to parental mRNA in eukaryotic cells. Millions of circRNAs have been detected by bioinformatics analyses of human tissue. The rapid development of RNA sequencing technology and bioinformatics has resulted in a plethora of diverse circRNAs being studied and characterized as regulators of physiological conditions and developmental stages. Many functions recognized for the circRNAs now include sequestering proteins from their native subcellular localization, regulating parental gene expression, and RNA-protein interactions. Besides, a role as miRNA sponges has been discovered, a function by which the circRNAs may act as competitive endogenous RNAs (ceRNAs) to affect gene expression by binding to and preventing target miRNAs from regulating their downstream target genes. Moreover, the affected circRNA/miRNA/mRNA axes underlie oncogenic and tumor suppressive properties.
Figure 1. Schematic diagram of the effects and mechanisms of circRNAs. (Lei B, et al. 2019)
Increasing evidence also shows that circRNAs may play a role in the development of some diseases, including atherosclerotic vascular disease risk, neurological disorders, osteoarthritis, multiple sclerosis, diabetes, Parkinson's disease, Alzheimer's disease, prion diseases, and schizophrenia. However, recent studies have discovered that circRNAs may be drawn into multiple types of cancer, including hepatocellular carcinoma (HCC), colorectal cancer (CRC), breast cancer and pancreatic ductal adenocarcinoma (PDAC). In addition to the peculiar expression in tissues, circRNAs are also found in saliva and exosomes, and it is believed that circRNAs are also regarded as a biological governor. In conclusion, circRNAs have the great potential to regulate the biological function and act as significant biomarkers to predict disease progression and prognosis, especially in tumor.
Due to the general features of circRNA including abundance, stability and specificity, circRNAs are considered to be suitable biomarkers for liquid biopsies. CircRNAs are enriched in body fluid including blood, saliva, cerebrospinal fluid, and urine. They can also be specifically detected in the free-floating cells inside these body fluids such as circulating blood cells and circulating tumor cells. In general, circRNAs are considered as a group of potential biomarkers especially for liquid biopsies, allowing early diagnosis, appropriate therapy selection, precise prognosis and frequent therapy monitoring for different types of diseases.
Figure 2. Potential application of circular RNAs as liquid biopsy biomarkers. (Zhang Z, et al. 2018)