Circular RNAs (circRNAs) are an enigmatic class of RNA in biologic systems. CircRNAs are generated from genomic transcripts by forming covalently-closed loops, thereby joining the 5 0 and 3 0 ends. With alternative splicing the same primary RNA transcript yields diverse circRNAs. Specifically, a splice donor site is joined to a splice acceptor site further upstream of the primary transcript, resulting in the production of a circular RNA. In human cells, circRNAs are usually composed of 1–5 exons, and the exon 2 is often the upstream “acceptor” exon. These circRNAs generated from exons and are called exonic circRNAs. However exonic circRNAs have not been shown to code for proteins thus being categorized as non-coding RNAs. There are also circRNAs that are generated from introns and thus named intronic circRNAs. Circularization of transcripts was previously believed to be the result of erroneous splicing processes within cells. This idea was challenged by the observation that circRNAs were detected in various cell types in an evolutionarily conserved manner. All circRNAs are predominantly found in the cytoplasm. The copy number of circRNAs can be up to 10 times greater than that of associated linear RNAs, suggesting that these circRNAs possess potential biologic functions rather than accidental errors during splicing. However, the function of circRNAs remains unclear until recently. Studies have shown that some circRNAs harbor multiple binding sites for microRNAs,“sponging” microRNAs thereby serving as competitive inhibitors for microRNA functions. For example, the circRNA circ-ITCH contains binding sites for miR-7, miR-17, and miR-214 and represses the activity of these microRNAs. 1 To serve as a sponge, however, a circular RNA has to contain many microRNA binding sites and be expressed at sufficiently high levels in cytoplasm. The majority of circRNAs may not be in this category and their functions remain uncertain.

Most recently the function of a circRNA named circ-Foxo3 was well studied by a research group in Toronto led by Burton Yang. Specifically, this group found that circ-Foxo3 was downregulated in patient tumor samples and in a group of cancer cells, whereas it was upregulated in the cancer cells when the cells were induced to undergo apoptosis. 2 The authors showed that silencing endogenous circ-Foxo3 produced an opposite effect, while ectopic circ-Foxo3