Biological roles and potential clinical values of circular RNAs in gastrointestinal malignancies

Abstract

Circular RNAs (circRNAs), a class of endogenous RNA molecules, are produced by alternative splicing of precursor RNA and are covalently linked at the 5' and 3' ends. Recent studies have revealed that dysregulated circRNAs are closely related to the occurrence and progression of gastrointestinal malignancies. Accumulating evidence indicates that circRNAs, including circPVT1, circLARP4, circ-SFMBT2, cir-ITCH, circRNA_100782, circ_100395, circ-DONSON, hsa_circ_0001368, circNRIP1, circFAT1(e2), circCCDC66, circSMARCA5, circ-ZNF652, and circ_0030235 play important roles in the proliferation, differentiation, invasion, and metastasis of cancer cells through a variety of mechanisms, such as acting as microRNA sponges, interacting with RNA-binding proteins, regulating gene transcription and alternative splicing, and being translated into proteins. With the characteristics of high abundance, high stability, extensive functions, and certain tissue-, time- and disease-specific expressions, circRNAs are expected to provide novel perspectives for the diagnoses and treatments of gastrointestinal malignancies.

Keywords: Circular RNA; biological function; clinical value; digestive system; gastrointestinal malignancies.

Figure 1

Biogenesis of circRNAs and the mechanisms of action of circRNAs. (A) Lariat-driven circularization (ecircRNA). (B) Intron-pairing-driven circularization (ecircRNA). (C) Circular intronic RNA. (D) Exon-intron-derived circRNA (EIciRNA). (E) RNA-binding protein (RBP)-driven circularization-derived circRNA. (F) The tRNA precursor-derived. (G) Other sources: fusion gene, circular DNA tumor virus, mitochondrial DNA-originated and mitochondria-encoded circular RNA (mecciRNA). (H) Functioning as miRNA sponges. (I) Interactions with RNA-binding proteins. (J) Involvement in alternative splicing regulation. (K) Regulation of parental gene transcription. (L) Protein-coding potential. QKI, Quaking; FUS, fused in sarcoma; ADAR1, adenosine to inosine acting on RNA enzyme 1; DHX9, DEAH-box helicase 9. IRES, internal ribosome entry site; ORF, open reading frame.

Figure 2

Clearance of circRNAs. (A) N6-methyladenosine-mediated degradation. (B) RNase L-mediated circRNA degradation after viral infection. (C) Argonaute protein 2 (AGO 2)-mediated degradation. (D) CircRNAs released in the form of extracellular vesicles. YTHDF2, YTH domain-containing family 2; HRSP12, heat-responsive protein 12; CCR4, carbon catabolite repression 4; MRP, multidrug resistance-associated protein; EMCV, encephalomyocarditis virus; RISC, RNA-induced silencing complex.

Figure 3

The relationships of circRNAs with gastrointestinal malignancies. (A) Cell proliferation, differentiation and cell cycle regulation. (B) Cell apoptosis regulation. (C) Cell metabolism regulation. (D) Immune escape. (E) Invasion and metastasis regulation. (F) Angiogenesis regulation. (G) Drug resistance regulation. EGFR, epidermal growth factor receptor; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; MAPK, mitogen-activated protein kinase; ERK, extracellular regulated protein kinases; KLF4, Krüppel-like factor4; NF-κB, nuclear transcription factor-κB; PTEN, phosphatase and tensin homology deleted on chromosome ten; CXCR4, C-X-C chemokine receptor type 4; ZEB1, zinc finger E-box binding protein 1; PTBP1, polypyrimidine tract-binding protein 1; PKLR, L-type pyruvate kinase; USP5, ubiquitin-specific peptidase 5; BRCA1, breast cancer type 1; bcl-2, B-cell lymphoma-2; HOXC6, homeobox C6; TET1, tet methylcytosine dioxygenases 1; S6K, S6 kinase; RBBP7, retinoblastoma-binding protein 7.