The potential of using blood circular RNA as liquid biopsy biomarker for human diseases

Abstract

Circular RNA (circRNA) is a novel class of single-stranded RNAs with a closed loop structure. The majority of circRNAs are formed by a back-splicing process in pre-mRNA splicing. Their expression is dynamically regulated and shows spatiotemporal patterns among cell types, tissues and developmental stages. CircRNAs have important biological functions in many physiological processes, and their aberrant expression is implicated in many human diseases. Due to their high stability, circRNAs are becoming promising biomarkers in many human diseases, such as cardiovascular diseases, autoimmune diseases and human cancers. In this review, we focus on the translational potential of using human blood circRNAs as liquid biopsy biomarkers for human diseases. We highlight their abundant expression, essential biological functions and significant correlations to human diseases in various components of peripheral blood, including whole blood, blood cells and extracellular vesicles. In addition, we summarize the current knowledge of blood circRNA biomarkers for disease diagnosis or prognosis.

Keywords: human diseases; liquid biopsy; peripheral blood circular RNA; translational biomarkers.

Figure 1

The biogenesis and function of circRNAs. (A) CircRNAs are formed by back-splicing of pre-mRNAs by different mechanisms, including: lariat driven circularization, intron pairing driven circulation, RBP driven circularization, and debranching escape of intron lariats. (B) CircRNAs can perform diverse biological functions. First, EIcircRNAs can interact with RNA Pol II and U1 snRNP to regulate gene transcription in the nucleus (i). Second, ecircRNAs can accumulate in the cytoplasm and act as miRNA decoys (ii), protein regulators (iii), and translation templates (iv). Third, circRNAs can be secreted into EVs by many cell types and transported to recipient cells by EVs. EV circRNAs can also act as important gene regulators

Figure 2

Peripheral blood circRNAs are implicated in human diseases and can be used as potential disease biomarkers in liquid biopsy. (A) Peripheral blood circRNAs are abundantly expressed and can be reliably detected in cell-free circulating blood components (such as exosomes, EVs, plasma, and serum) and blood cells (including PBMCs, macrophages, RBCs, and platelets). (B) Some exosomal circRNAs, such as circ-DB (i), circSHKBP1 (ii), and circUHRF1 (iii), are important regulators in oncogenic pathways, while some circRNAs in exosomes, such as circHIPK3 (iv), play key roles in the release of inflammatory cytokines. (C) Peripheral blood circRNAs, both cell-free circRNAs and intracellular circRNAs in blood cells, have potential clinical applications as liquid biopsy biomarkers in many human diseases, such as the diagnosis, prognosis and treatment guidance of many human diseases, including autoimmune diseases, cancers, cardiovascular diseases, immuno-deficiency diseases, infectious diseases, and neurodegenerative diseases

Figure 3

CircRNAs are actively involved in host immune responses to exogenous pathogens. (A) CircRasGEF1B, a circRNA induced by LPS, can protect cells from bacterial infection by regulating the expression of ICAM-1 mRNA in the TLR4/LPS pathway. (B) Exogenous circRNAs released by viruses can be recognized by RIG-I, thus activating the host innate immunity to viruses (i). Moreover, NF90/NF110 not only promotes circRNA production in the nucleus but also interacts with mature host circRNAs to form circRNP complexes in the cytoplasm. Upon viral infection, NF90/NF110 can be released from circRNP complexes and bind viral mRNAs to inhibit viral replication (ii). In addition, circRNAs can form RNA duplexes and act as inhibitors of PKR under normal conditions. When a virus invades the cells of its host, RNase L is activated to efficiently degrade circRNAs, and PKR is released and activated to initiate the early cellular innate immune response (iii)