Circular RNAs: an emerging landscape in tumor metastasis

Abstract

Circular RNAs (CircRNAs), the endogenous long noncoding RNAs, unlike linear RNAs, are structurally continuous, covalently closed loops without 5' cap or 3' polyadenylated tail. High-throughput RNA sequencing has enabled the discovery of several endogenous circRNAs in different species and tissues. The circRNAs mainly act as sponges to cytoplasmic microRNA, aid in protein translation, or interact with RNA-binding proteins to generate RNA-protein complexes which control transcription. Recently, circRNAs have been reported to participate in cancer pathogenesis, particularly tumor metastasis in humans, mainly due to their frequent aberrant expression in cancers. However, the detail molecular mechanism of circRNAs activity in tumor metastasis is still elusive. Some specifically expressed circRNAs can potentially be used as biomarkers and therapeutic targets for tumor treatment. Further understanding of the network interactions and regulation of circRNAs is paving the way for the identification of better therapeutic strategies in tumor metastasis. In this mini review, we have summarized the current state of research on functions and mechanisms of novel circRNAs that regulate tumorigenesis and have evaluated the relationship between dysregulation of circRNAs and tumor metastasis.

Keywords: Circular RNAs; DNA demethylation; back-splicing; epithelial-mesenchymal transition; exosomes; tumor metastasis.

Figure 1

Biosynthesis of circRNAs. Various mechanisms are involved for generating different circRNAs types. A. Intron-pairing-driven circularization, involves the complementarity between the introns on either side of pre-mRNA. B. Lariat-driven circularization, involves formation of exonic circRNAs or EIciRNAs that does/does not involve intron removal with skipping of the exon along with RNA folding. C. Binding to the introns at specific sequences to influence circRNA biogenesis. D. CircRNA biogenesis involves the formation of lariat between conserved motifs at various combinations located upstream/downstream of introns. E. Formation of circular RNA (triRNA) by splicing of the pre-tRNA into two parts, with a 3’-5’ phosphodiester bond bound in one. F. Canonical pre-mRNA splicing and mRNA biogenesis.

Figure 2

Multiple functions of circRNAs. A. A section of circRNAs are vitally involved in protein-coding. Encoding of proteins by circRNAs is also possible with an internal ribosome entry site (IRES). B. A majority of circRNAs function as microRNA (miRNA) sponges that interact with miRNA-Ago2 complexes to cause inhibition of miRNA functions. C. CircRNAs bind RBPs to form RNA-protein complexes to affect their functions and translocations. D. Transcriptional regulation. ElcircRNA and ciRNA can cause induction of transcription of parental genes by binding transcription complexes at the host promoters.

Figure 3

Mechanism of circRNAs activity in tumor metastasis. A. CircRNAs function as miRNA sponges to promote the EMT signaling pathway via lowering of E-cadherin and increasing N-cadherin and vimentin. B. CircRNAs could recruit demethylase and induce DNA demethylation in the CpG islands to promote tumor cell metastasis. C. The presence of circRNAs in exosomes might promote tumor metastasis by promoting cancer cell’s EMT.