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Circular RNAs: implications of signaling pathways and bioinformatics in human cancer
Affiliations
- PMID: 36861443
- PMCID: PMC9978890
- DOI: 10.20892/j.issn.2095-3941.2022.0466
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Review
Circular RNAs: implications of signaling pathways and bioinformatics in human cancer
Cancer Biol Med.
.
Abstract
Circular RNAs (circRNAs) form a class of endogenous single-stranded RNA transcripts that are widely expressed in eukaryotic cells. These RNAs mediate post-transcriptional control of gene expression and have multiple functions in biological processes, such as transcriptional regulation and splicing. They serve predominantly as microRNA sponges, RNA-binding proteins, and templates for translation. More importantly, circRNAs are involved in cancer progression, and may serve as promising biomarkers for tumor diagnosis and therapy. Although traditional experimental methods are usually time-consuming and laborious, substantial progress has been made in exploring potential circRNA-disease associations by using computational models, summarized signaling pathway data, and other databases. Here, we review the biological characteristics and functions of circRNAs, including their roles in cancer. Specifically, we focus on the signaling pathways associated with carcinogenesis, and the status of circRNA-associated bioinformatics databases. Finally, we explore the potential roles of circRNAs as prognostic biomarkers in cancer.
Keywords: bioinformatics; cancer; circRNA; database; signaling pathway.
Copyright © 2023 Cancer Biology & Medicine.
Conflict of interest statement
No potential conflicts of interest are disclosed.
Figures
Biogenesis, mechanisms, and functions of circRNAs in cancer. (A) Intron base-pairing-driven circularization. (B) RBP-driven circularization. Looping of the introns (containing the splice donor site and splice acceptor site) flanked by exons is required for back-splicing. This looping can be facilitated by base-paring of complementary sequences between inverse-repeat Alu elements (A) or by RBP dimerization (B). RBPs bind intron-flanking introns and promote circularization of the pre-mRNA (or lariat), thus generating circRNAs. (C) GU/C-rich sequence-driven circularization. Pre-mRNAs comprising a 7-nucleotide (nt) GU-rich element and an 11-nt C-rich element consensus motif facilitate the generation of circRNAs. (D) Pre-tRNAs generate tricRNAs. An intron-containing pre-tRNA is cleaved by the tRNA spicing endonuclease (TSEN) complex, thus generating a tricRNA at the bulge-helix-bulge (BHB) motif; the intron termini then ligate and form a tricRNA. (E) circRNAs interact with Pol II, thereby regulating parental gene transcription and splicing. Competition between linear splicing and back-splicing of the pre-mRNA influences the balance between the 2 types of splicing. (F) circRNAs interact with proteins in several ways. circRNAs act as scaffolds that facilitate interactions between enzymes with their substrates. circRNAs can also recruit proteins to specific loci and promote protein assembly. (G) circRNAs function as miR and protein sponges. circRNAs containing miR response elements (MREs) can regulate miR-target mRNA expression through miR sequestration (or “sponging”). A highly expressed circRNA with many MREs is likely to function as an miR sponge and to positively regulate target mRNA translation. circRNAs containing binding motifs for RBPs might sponge these proteins and regulate their functions. (H) m6A and IRES-driven circRNA translation. A subset of circRNAs containing IRES and/or m6A modifications can serve as templates for translation and give rise to circRNA-specific peptides with the ORF crossing the back-splicing junctions. (I) circRNA transport via exosomes. circRNAs can be loaded into exosomes, thereby forming exo-circRNAs, which function as messengers in intercellular communication through the horizontal transfer of their cargo molecules to recipient cells.
The molecular roles of circRNAs in the PI3K/AKT/mTOR signaling pathway. The PI3K/AKT/mTOR pathway is the most commonly activated pathway in human cancers. Receptor tyrosine kinase activation and tyrosine phosphorylation of its cytosolic domain or its scaffolding adaptors create binding sites that recruit the lipid kinase PI3K—a regulator of signaling and intracellular vesicular trafficking and cellular processes such as proliferation, survival, and protein synthesis—to the plasma membrane. circRNAs commonly act as ceRNAs of miRs in tumor progression, thus inhibiting the functions of miRs. Nine upregulated and 6 downregulated circRNAs are indicated; 12 circRNAs regulate the PI3K/AKT/mTOR pathway through ceRNA effects. Red: upregulated circRNAs; blue: downregulated circRNAs.
Molecular roles of circRNAs in the Wnt/β-catenin signaling pathway. The Wnt pathway is critical for various cellular functions, such as ensuring cell polarity, movement, and proliferation; this pathway is also often involved in cancer progression. A destruction complex initially phosphorylates and then ubiquitinates β-catenin in the cytoplasm, and subsequently inhibits Wnt signaling. circRNAs regulate the β-catenin destruction complex, thereby activating or suppressing the nuclear downstream targets of Wnt signaling. circRNA competition with the endogenous RNAs (ceRNAs) of miRs is their main mechanism of regulating the Wnt signaling pathway. The IRES-driven translation of novel proteins from circRNAs is another crucial mechanism of circRNAs in Wnt signaling. Eleven upregulated and 5 downregulated circRNAs are shown; 8 of these circRNAs regulate the Wnt pathway through ceRNA effects. Red: upregulated circRNAs; blue: downregulated circRNAs; β-cat: β-catenin.
The molecular roles of circRNAs in the Notch signaling pathway. The Notch pathway is responsible for neurogenesis, angiogenesis, and cell proliferation, and it directly couples events at the cell membrane with the regulation of transcription. Notch receptors bind specific ligands, thus resulting in sequential cleavage of the Notch receptor and the release of the Notch intracellular domain (NICD) into the signal-receiving cell. The NICD containing the nuclear localization sequence translocates to the nucleus. The NICD interacts with the CBF-1/Su(H)/LAG1 (CSL) transcription factor and subsequently induces the recruitment of the transcriptional co-activator (Co-A) Mastermind-like (MAML) and other transcriptional Co-As. All 4 receptors (Notch1–4) mediate canonical signaling by activating CSL-dependent transcription and are involved in cancers. Six upregulated and one downregulated circRNAs are shown; 7 circRNAs regulate the Notch pathway through ceRNA effects. Red: upregulated circRNAs; blue: downregulated circRNAs.
Molecular roles of circRNAs in the Hippo signaling pathway. The Hippo pathway is an evolutionarily conserved signaling pathway with key roles in various diseases, most notably cancer. The Hippo kinase cascade converges on its nuclear effector YAP/TAZ and regulates gene expression programs. YAP/TAZ phosphorylation by Hippo signaling inactivates YAP/TAZ transcriptional coactivators by excluding them from the nucleus and promotes YAP/TAZ degradation. When Hippo signaling is low, YAP/TAZ enters the nucleus, where it drives gene expression. Five upregulated and 3 downregulated circRNAs are indicated; 4 circRNAs regulate the Hippo pathway through ceRNA effects. Red: upregulated circRNAs; blue: downregulated circRNAs.
The molecular roles of circRNAs in the p53/Bcl-2 signaling pathway. p53 is a common tumor suppressor gene that regulates the cell cycle and apoptosis through various pathways. A direct interaction between p53 and circRNAs preserves p53 by preventing its ubiquitination by E3 ubiquitin ligases (such as MDM2). circRNAs also affect the downstream targets of p53, such as Bcl-2 or Bcl-2/caspase, which mediates apoptosis and is involved in tumor development. Nine upregulated and 5 downregulated circRNAs are indicated; 7 circRNAs regulate the p53/Bcl-2 signaling pathway through ceRNA effects. Red: upregulated circRNAs; blue: downregulated circRNAs.
Molecular roles of circRNAs in the TGF-β/Smad signaling pathway. TGF-β signaling occurs via membrane-bound heteromeric serine-threonine kinase receptor complexes that are activated by TGF-β ligands and the subsequent phosphorylation of Smad family members. Smad members accumulate in the nucleus and act as transcription factors regulating target gene expression. Activation of canonical TGF-β signaling represses epithelial gene expression, and the resulting TGF-β-induced EMT has a central role in cancer metastasis. Three upregulated and 4 downregulated circRNAs are indicated; 4 circRNAs regulate the TGF-β/Smad pathway through ceRNA effects. Red: upregulated circRNAs; blue: downregulated circRNAs.
References
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- Kristensen LS, Jakobsen T, Hager H, Kjems J. The emerging roles of circRNAs in cancer and oncology. Nat Rev Clin Oncol. 2022;19:188–6. - PubMed