A recent review, published in Protein & Cell, has explored the potential use of blood circular RNA as a liquid biopsy biomarker for human diseases.
Liquid biopsy has advantages over traditional tissue biopsy methods, as it is non-invasive, can be performed in real-time and is also highly accurate. It has become a revolutionary tool in disease management, supporting diagnosis, prognosis and treatment guidance. Liquid biopsy biomarkers are vital for precision medicine. As a result, a lot of studies have begun exploring the use of circular RNAs as liquid biopsy biomarkers for human diseases.
Circular RNA (circRNA) is a novel class of single-stranded RNA with a closed loop structure. They are endogenous noncoding RNA molecules. Most circRNAs are formed by a back-splicing process during pre-mRNA splicing. There are three major types of circRNAs – exonic (ecircRNAs), exon-intron (EI-circRNAs) and circular intronic (cirRNAs). They have been identified in almost all organisms across the eukaryotic tree of life. However, the functional characterisation of circRNAs is still in its infancy.
Several studies have revealed many regulatory roles and cellular functions that circRNAs can perform. CircRNAs have diverse functions as miRNA decoys, protein regulators and translation templates. Most importantly, researchers have found that aberrant expression of circRNAs can be associated with many human diseases, including cancer, neurodegenerative diseases, cardiovascular disease and immune diseases. Due to their high stability, abundant expression and high specificity, circRNAs are becoming promising biomarkers for human disease.
Role of circular RNA in disease
Researchers have found that dysregulation of circRNA generation or turnover may lead to aberrant circRNA expression in cells or tissues. This aberrant expression is thought to be linked to many human diseases.
A good biomarker that has clinical significance must meet the criteria of analytical validity, clinical validity and clinical utility. CircRNAs have several advantages over canonical linear RNAs as disease biomarkers. Firstly, circRNAs are more stable than linear RNAs because they have closed loops structures without 5’ and 3’ ends. Secondly, circRNAs are abundantly expressed in many tissue samples, particularly brain and human blood samples. Thirdly, circRNAs are expressed in a tissue-specific and developmental stage-specific manner.
To date, many circRNAs have been identified as potential biomarkers for human diseases, particular in relation to cancer. For example, Cdr1as overexpression strongly inhibits the activity of the tumour suppressor miR-7. There is growing evidence demonstrating a significant increase in Cdr1as in colorectal cancer samples. Therefore, Cdr1as has been revealed as a prognostic biomarker in colorectal cancer patients. In order to improve biomarker accessibility, circRNA biomarkers in bodily fluids are considered better for clinical application.
Blood circRNAs can be classified into blood cell-free circRNAs and circRNAs in blood cells. Blood cell-free circRNAs are secreted from different tissue cells into the blood. Therefore, they have corresponding tissue origins and represent their clinical significance in the original tissue. Whereas blood cell circRNAs consist of circRNAs in various blood cells e.g. monocytes and neutrophils. This is an important indicator of host immune status.
In the past few years, several studies have shown the promise of blood circRNAs as biomarkers of many human diseases in liquid biopsy. However, many issues need to be considered before they can be translated into clinical practice. The methods to discover and profile circRNAs are far from optimal. Future studies need to test the analytical performance of different circRNA profiling methods in clinical blood samples. In addition, more clinical samples are required to validate the sensitivity and specificity of identified biomarkers in larger cohorts. Particularly, their performance in discriminating patients with similar clinical phenotypes. Lastly, further work needs to be done to test and validate the usefulness of these biomarkers in clinical practice i.e. their ability to inform clinical decisions and improve outcomes. Nonetheless, the potential of translating blood circRNA biomarkers into clinical practice brings about new hope and exciting options for liquid biopsy.
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