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Review
. 2020 May;77(9):1661-1680.
doi: 10.1007/s00018-019-03345-5. Epub 2019 Oct 28.

CircRNA: a rising star in gastric cancer

Rong Li  1   2 , Jiajia Jiang  1 , Hui Shi  2 , Hui Qian  1   2 , Xu Zhang  3   4 , Wenrong Xu  5   6
Affiliations
Review

CircRNA: a rising star in gastric cancer

Rong Li et al. Cell Mol Life Sci. 2020 May.

Abstract

In recent years, a large number of circRNAs have been identified in mammalian cells with high-throughput sequencing technologies and bioinformatics. The aberrant expression of circRNAs has been reported in many human diseases including gastric cancer (GC). The number of GC-related circRNAs with validated biological functions and mechanisms of action is growing. CircRNAs are critically involved in GC cell proliferation, apoptosis, migration, and invasion. CircRNAs have been shown to function as regulators of parental gene transcription and alternative splicing and miRNA sponges. Moreover, circRNAs have been suggested to interact with proteins to regulate their expression level and activities. Several circRNAs have been identified to encode functional proteins. Due to their great abundance, high stability, tissue- and developmental-stage-specific expression patterns, and wide distribution in various body fluids and exosomes, circRNAs exhibit a great potential to be utilized as biomarkers for GC. Herein, we briefly summarize their biogenesis, properties and biological functions and discuss about the current research progress of circRNAs in GC with a focus on the potential application for GC diagnosis and therapy.

Keywords: Biomarker; CircRNA; Gastric cancer; Therapeutic target; miRNA sponge.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Biogenesis of circRNA. a Canonical splicing. Pre-mRNA is spliced by spliceosome to remove intervening introns and leave only exons sequentially connected to form mature mRNA. The rest lariat intron can escape debranching and degradation with 7 nt GU-rich sequences near the 5′ splice site and 11 nt C-rich sequence near branch site and instead the 3′ “tail” downstream sequence is trimmed to form stable ciRNA. b Lariat-driven circularization. A downstream 5′ splice site of exon 4 is joined to an upstream 3′ splice site of exon 1 forming lariat structure. And then, the lariat containing skipped exons undergoes internal splicing of one intron to form EIciRNA or splicing of two introns to form ecircRNA. c Intron-pairing-driven circularization. Intronic motifs flanking circularized exon 2 and 3 have considerably complementary sequences which bring splicing sites close to form EIciRNA or eciRNA. RNA binding proteins (RBPs) driven circularization. RBPs with binding sites on flanking introns of exons 2 and 3 could bring two splicing sites close together to facilitate circularization. d The tRNA splicing endonuclease complex (TSEN) recognizes bulge–helix–bulge (BHB) motif and carries out intron excision of pre-tRNA and then release and ligate the end to form tRNA and tricRNA
Fig. 2
Fig. 2
Functions and mechanisms of circRNA. a circRNAs’ backsplicing process forms three types of circRNAs and competes with linear RNAs’ canonical splicing to maintain the transcripts dynamic balance. Mature mRNA could be translated into proteins or inhibited by miRNAs which bound with Argonauto 2 (AGO2) protein. b CiRNAs accumulate to transcription sites and promote transcription by regulating elongation Pol II machinery. c EIciRNAs located in nucleus bind to U1 snRNA and form EIciRNA–U1 snRNP complexes to enhance gene transcription by interacting with Pol II transcription complex at the promoters of parental genes. d EcircRNAs exported into cytoplasm share some miRNA binding sites and sponge miRNAs to inhibit their effects on mRNA. e CircRNAs containing extensive m6A modification are sufficient to drive translation of circRNAs in a cap-independent fashion. f CircRNA (circANRIL) binds to PES1 which is essential to 36S and 32S pre-rRNA processing to mature 5.8S and 28S rRNA and thus impair exonuclease-mediated pre-rRNA processing and ribosome biogenesis. g CircRNAs could be packaged into exosomes and exported to extracellular space or circulating system
Fig. 3
Fig. 3
The role and regulatory pathway of GC-related circRNAs. The schematic diagram depicts the known role of circRNAs in GC progression and the way that circRNAs involved in miRNA-associated gene regulatory pathway
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