Circular RNAs as Urinary Biomarkers

Circular RNAs (circRNAs)3 bear a unique topological feature of circularity among the RNA species. CircRNAs, together with other RNA species without protein-coding potential, are grouped as noncoding RNAs (1). They are single-stranded, covalently closed circular RNA molecules and are hypothesized to be mainly generated through back-splicing of exons from precursor messenger RNAs. CircRNAs were once considered to be aberrant splicing by-products that were only present in minute amounts in cells. With specific molecular assay design (enrichment of circRNAs through depletion of linear RNAs in the sequence library), advances in sequencing technologies, and specialized bioinformatics algorithms for identification of back-spliced junctions, global profiling of circRNAs (2) has now become feasible and circRNAs are shown to be widespread in diverse cell types. Researchers have been trying to understand the biological function of circRNAs. These molecules might be indirectly involved in gene regulation as competing endogenous RNAs or microRNA sponges. The potential of this RNA species as a disease biomarker is to be explored. There are a few biological properties of circRNAs that make them suitable for biomarker development. First, the circular topology and lack of open ends of circRNAs confer certain resistance to exoribonuclease-mediated RNA degradation. CircRNAs have been shown to be more stable than their linear counterparts (1). Second, as mentioned above, some circRNAs are abundant in the various human cell types (3). Third, the circRNA expression patterns are diverse among different cell types and could exhibit tissue specificity. In a recent large-scale study involving circRNA profiling of over 800 tumor tissue samples of 17 different cancer types (4), hundreds of circRNAs were suggested to be tissue-specific and/or cancer-specific. The researchers proposed that the tissue specificity of these circRNAs could be attributed to the tissue specificity of the “parental” gene. Previous studies have demonstrated the presence of cell-free circRNAs in …