Circular RNAs in cancer: opportunities and challenges in the field

Abstract

Circular RNA (circRNA) is a novel member of the noncoding cancer genome with distinct properties and diverse cellular functions, which is being explored at a steadily increasing pace. The list of endogenous circRNAs involved in cancer continues to grow; however, the functional relevance of the vast majority is yet to be discovered. In general, circRNAs are exceptionally stable molecules and some have been shown to function as efficient microRNA sponges with gene-regulatory potential. Many circRNAs are highly conserved and have tissue-specific expression patterns, which often do not correlate well with host gene expression. Here we review the current knowledge on circRNAs in relation to their implications in tumorigenesis as well as their potential as diagnostic and prognostic biomarkers and as possible therapeutic targets in future personalized medicine. Finally, we discuss future directions for circRNA cancer research and current caveats, which must be addressed to facilitate the translation of basic circRNA research into clinical use.

Figure 1

Mechanisms of circRNA biogenesis. (a) Efficient back splicing and circRNA generation requires that the 3′-end of an exon be located in close proximity to an upstream 5′-end of the same or another exon. This may be facilitated by the formation of a looping structure held in place by complementary base pairing of the RNA, for example, due to the presence of flanking reverse complementary Alu repeats. Alternatively, the looping structure may be held in place by binding of dimerizing RNA binding proteins with corresponding binding motifs present in the flanking regions. The small arrows indicate the back-splicing junctions of the circular splicing products. (b) Alternatively, circRNAs can be generated from an exon-containing lariat precursor created by an exon-skipping event followed by internal splicing depending on the kinetics of splicing versus debranching and exonuclease-mediated degradation.

Figure 2

Putative functions of circRNAs in cancer. (a) Many circRNAs are likely to function as miRNA sponges or decoys. Binding of miRNAs to circRNAs may release target mRNAs from miRNA-dependent degradation resulting in more efficient translation. (b) Exon–intron circRNAs have been shown to associate with RNA pol II and enhance the transcription of their parental genes via interaction with U1 snRNP. Splicing and transcription of many genes may also be indirectly regulated through a competition between canonical splicing and back splicing. However, it is largely unknown which factors may impinge on the balance between circRNA and canonical linear splicing. (c) CircRNAs with binding motifs for an enzyme and its substrate may function as scaffolds facilitating co-localization and reaction kinetics. (d) CircRNAs with RNA-binding protein-binding motifs may function as sponges or decoys for proteins and thereby regulate their activity. (e) CircRNAs with IRES elements and AUG sites may, under certain circumstances, be used as templates for translation; however, it is currently unknown if this has any relevance in cancer.

Figure 3

Circular RNAs involved in the hallmarks of cancer. Tumor-suppressor circRNAs are indicated in green and circRNAs with oncogenic properties are indicated in black.