Circular RNAs function as ceRNAs to regulate and control human cancer progression

Molecular Cancer, Journal Year: 2018, Volume and Issue: 17(1)

Published: April 7, 2018

Circular RNAs (circRNAs) are connected at the 3′ and 5′ ends by exon or intron cyclization, forming a complete ring structure. circRNA is more stable conservative than linear RNA abounds in various organisms. In recent years, increasing numbers of reports have found that plays major role biological functions network competing endogenous (ceRNA). circRNAs can compete together with microRNAs (miRNAs) to influence stability target their translation, thus, regulating gene expression transcriptional level. involved processes such as tumor cell proliferation, apoptosis, invasion, migration ceRNAs. circRNAs, therefore, represent promising candidates for clinical diagnosis treatment. Here, we review progress studying ceRNAs tumors highlight participation signal transduction pathways regulate cellular functions.

Language: Английский

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The interaction of circRNAs and RNA binding proteins: An important part of circRNA maintenance and function

Journal of Neuroscience Research, Journal Year: 2018, Volume and Issue: 98(1), P. 87 - 97

Published: Dec. 21, 2018

Abstract The widespread expression of circular RNAs (circRNAs) is regarded as a feature gene in highly diverged eukaryotes. Recent studies have shown that circRNAs can act miRNA sponge to repress function, participate splicing target genes, translate genes into protein and interact with RNA binding proteins (RBPs). RBPs are broad class involved transcription translation, interaction considered an important part circRNA which serve essential element underlying the functions circRNAs, including genesis, transcriptional regulation extracellular transport. In this mini‐review, we attempt explore detail relationship between RBPs, interactions two factors. goal review investigate emerging better understand how their alters cellular function.

Language: Английский

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Emerging role of exosomes in cancer progression and tumor microenvironment remodeling

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: June 28, 2022

Abstract Cancer is one of the leading causes death worldwide, and factors responsible for its progression need to be elucidated. Exosomes are structures with an average size 100 nm that can transport proteins, lipids, nucleic acids. This review focuses on role exosomes in cancer therapy. We discuss how able modulate components tumor microenvironment influence proliferation migration rates cells. also highlight that, depending their cargo, suppress or promote cell enhance reduce response radio- chemo-therapies. In addition, we describe trigger chronic inflammation lead immune evasion by focusing ability transfer non-coding RNAs between cells other molecular signaling pathways such as PTEN PI3K/Akt cancer. Subsequently, use carriers anti-tumor agents genetic tools control progression. then tumor-derived carcinogenesis. Finally, devote a section study diagnostic prognostic clinical courses important treatment patients. provides comprehensive understanding therapy, therapeutic value remodeling microenvironment. Graphical

Language: Английский

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Molecular Mechanisms Driving mRNA Degradation by m6A Modification

Trends in Genetics, Journal Year: 2020, Volume and Issue: 36(3), P. 177 - 188

Published: Jan. 18, 2020

N6-Methyladenosine (m6A) as an mRNA modification plays multiple roles in various steps/characteristics of processing and metabolism, such splicing, export, translation, stability.YTHDF2 preferentially recognizes m6A recruits RNA-degrading enzymes or adaptor proteins to trigger rapid degradation the m6A-containing mRNA.Depending on presence HRSP12-binding sites mRNAs, YTHDF2 elicits one two RNA decay pathways: deadenylation by YTHDF2–CCR4/NOT deadenylase complex endoribonucleolytic cleavage via YTHDF2–HRSP12–RNase P/MRP complex.The stability mRNAs is regulated dynamic crosstalk between other cellular factors, RNA-binding proteins, structures, and/or types modification. (m6A), most prevalent internal associated with eukaryotic influences many steps including well stability. Recent studies have revealed that undergo distinct pathways degradation: YT521-B homology (YTH) domain-containing family protein 2 (YTHDF2; reader protein)–CCR4/NOT (deadenylase) YTHDF2–HRSP12–ribonuclease (RNase) P/mitochondrial RNA-processing (MRP) (endoribonuclease) complex. Some circular RNAs (circRNAs) are also subject P/MRP. Here, we highlight recent progress molecular mechanisms underlying describe our current understanding regulation m6A-mediated through (or YTHDF2) factors. Many point role a mode post-transcriptional gene this field has been termed 'epitranscriptomics' [1.Roundtree I.A. et al.Dynamic modifications expression regulation.Cell. 2017; 169: 1187-1200Abstract Full Text PDF PubMed Scopus (836) Google Scholar, 2.Kadumuri R.V. Janga S.C. Epitranscriptomic code its alterations human disease.Trends Mol. Med. 2018; 24: 886-903Abstract (49) 3.Esteller M. Pandolfi P.P. The epitranscriptome noncoding cancer.Cancer Discov. 7: 359-368Crossref (78) 4.Meyer K.D. al.Comprehensive analysis methylation reveals enrichment 3′ UTRs near stop codons.Cell. 2012; 149: 1635-1646Abstract (1634) Scholar]. To date, approximately 150 species, tRNAs, rRNAs, (ncRNAs), viral genomes [5.Helm Motorin Y. Detecting epitranscriptome: predict validate.Nat. Rev. Genet. 18: 275-291Crossref (249) 6.Boccaletto P. al.MODOMICS: database pathways. 2017 update.Nucleic Acids Res. 46: D303-D307Crossref (654) 7.Nachtergaele S. He C. Chemical life transcript.Annu. 52: 349-372Crossref (66) In review, summarize reports deposition function. particular, discuss findings regarding how contributes at level. Although first discovered 1970s, recently returned spotlight development RNA-seq techniques characterization involved [4.Meyer Scholar,8.Dominissini D. al.Topology mouse methylomes m6A-seq.Nature. 485: 201-206Crossref (1829) This found expressed mammalian cell blood, muscle, liver, intestinal, neuronal cells. At level, functions almost all stages cycle, regulates (Figure 1). implicated variety physiological events spermatogenesis [9.Lin Z. al.Mettl3-/Mettl14-mediated N6-methyladenosine modulates murine spermatogenesis.Cell 27: 1216-1230Crossref (119) Scholar], embryogenesis [10.Wang al.N6-methyladenosine embryonic neural stem self-renewal histone modifications.Nat. Neurosci. 21: 195-206Crossref (125) cortical neurogenesis [11.Yoon K.J. al.Temporal control methylation.Cell. 171: 877-889.e817Abstract (266) carcinogenesis [12.Barbieri I. al.Promoter-bound METTL3 maintains myeloid leukaemia m6A-dependent translation control.Nature. 552: 126-131Crossref (366) 13.Choe J. al.mRNA circularization METTL3-eIF3h enhances promotes oncogenesis.Nature. 561: 556-560Crossref (191) 14.Lin al.The methyltransferase cancer cells.Mol. Cell. 2016; 62: 335-345Abstract (559) As modification, 25% harbor more bases general, enriched around codons untranslated region (UTR) Scholar,15.Linder B. al.Single-nucleotide-resolution mapping m6Am throughout transcriptome.Nat. Methods. 2015; 12: 767-772Crossref (590) although varies among different mRNAs. Accumulating evidence indicates reversible event coordinated action methyltransferases (m6A writers) demethylases erasers) depletion Methyltransferase-like 3 (METTL3) (see Glossary), known MT-A70, METTL14 function catalytic core m6A–METTL (MAC). DRACH motif (where D = A, G, U; R purine; H C, U) introduces into nascent transcripts Notably, activity, whereas forms heterodimer binding target [16.Scholler E. al.Interactions, localization, phosphorylation generating METTL3–METTL14–WTAP complex.RNA. 499-512Crossref (118) 17.Sledz Jinek Structural insights mechanism writer complex.eLife. 5e18434Crossref (195) 18.Wang al.Structural basis for cooperative Mettl3 Mettl14 methyltransferases.Mol. 63: 306-317Abstract (341) activity MAC conjunction regulatory – m6A–METTL-associated (MACOM) comprising Wilms tumor 1-associated (WTAP) (also female-lethal[2]d), 15 (RBM15), Vir-like methyltransferase-associated (VIRMA) Virilizer KIAA1429), Cbl proto-oncogene-like 1 (CBLL1) Hakai), zinc-finger CCCH-type-containing 13 (ZC3H13) [19.Lence T. al.Mechanistic enzymes.Biochim. Biophys. Acta. 2019; 1862: 222-229Crossref (37) MACOM itself lacks interaction components localization specific RBM15 paralog RBM15B interact WTAP-dependent manner bind U-rich sequences [20.Patil D.P. al.m6A XIST-mediated transcriptional repression.Nature. 537: 369-373Crossref (572) Scholar,21.Knuckles al.Zc3h13/Flacc required adenosine bridging mRNA-binding factor Rbm15/Spenito machinery component Wtap/Fl(2)d.Genes Dev. 32: 415-429Crossref (170) result, recruit MAC–WTAP proximal consensus motifs. It suggested VIRMA mediates participates alternative polyadenylation association CFIm (a tetramer CPSF5 CPSF6) RNA-dependent [22.Yue al.VIRMA preferential 3′UTR codon associates polyadenylation.Cell 4: 10Crossref (223) Depletion induces lengthening, reduced amount By contrast, leads shortening 3′UTR, increased abundance codons. Considering defined cytoplasm, lengthening occurs nucleus, details VIRMA-mediated should be investigated future studies. ZC3H13 nuclear ZC3H13–WTAP–VIRMA–CBLL1 cells [23.Wen al.Zc3h13 self-renewal.Mol. 69: 1028-1038.e1026Abstract (242) serves adapter WTAP RBM15, enable efficient [21.Knuckles now established installed cotranscriptionally Scholar,24.Knuckles al.RNA fate determination cotranscriptional microprocessor binding.Nat. Struct. Biol. 561-569Crossref (72) 25.Ke deposited pre-mRNA not splicing but do specify cytoplasmic turnover.Genes 31: 990-1006Crossref (221) 26.Slobodin al.Transcription impacts efficiency co-transcriptional N6-adenosine 326-337.e312Abstract (182) CCAAT/enhancer-binding zeta (CEBPZ) binds transcription start site promoter independent METTL14, thereby inducing protein-coding recruited chromatin transcription-dependent methylates [24.Knuckles report showed conversion A m6As depends polymerase II. low rate elongation greater number transcript [26.Slobodin Furthermore, it majority formed exon chromatin-associated during [25.Ke possible reversibility was demonstrated identification demethylases: α-ketoglutarate-dependent dioxygenase alk B homolog 5 (ALKBH5) fat mass obesity-associated (FTO) [27.Jia G. al.N6-Methyladenosine major substrate FTO.Nat. Chem. 2011; 885-887Crossref (1512) Scholar,28.Zheng al.ALKBH5 demethylase metabolism fertility.Mol. 2013; 49: 18-29Abstract (1256) ALKBH5 demethylates motif-dependent manner, FTO broad spectrum substrates [28.Zheng Therefore, plausible than global demethylation. originally overweight obesity humans [29.Dina al.Variation childhood severe adult obesity.Nat. 2007; 39: 724-726Crossref (1129) Scholar,30.Frayling T.M. al.A common variant body index predisposes obesity.Science. 316: 889-894Crossref (2997) Later, shown demethylate polyadenylated Scholar,31.Fu al.FTO-mediated formation N6-hydroxymethyladenosine N6-formyladenosine RNA.Nat. Commun. 1798Crossref (208) several provided results upregulation total Scholar,32.Zhao X. al.FTO-dependent demethylation adipogenesis.Cell 2014; 1403-1419Crossref (459) suggest N6,2′-O-dimethyladenosine (m6Am), which adjacent 7-methylguanosine cap affects [33.Mauer al.Reversible 5′ controls stability.Nature. 541: 371-375Crossref (425) More recently, N1-methyladenosine (m1A) tRNAs [34.Wei al.Differential m6A, m6Am, m1A mediated nucleus cytoplasm.Mol. 71: 973-985.e975Abstract (193) gene-regulatory biological effects summarized review papers [35.Shi H. al.Where, when, how: context-dependent writers, readers, erasers.Mol. 74: 640-650Abstract (284) Scholar,36.Delaunay Frye regulating cancer.Nat. Cell 552-559Crossref (93) noted these involving mostly m6A-recognizing (RBPs) proteins), YTH (YTHDF1, YTHDF2, YTHDF3, YTHDC1, YTHDC2), initiation 3, heterogeneous ribonucleoprotein (hnRNP) hnRNP hnRNPA2B1. decay. destabilization identified uncovered increase half-life after (METTL3 WTAP) downregulation both [37.Batista P.J. transition cells.Cell Stem 15: 707-719Abstract (549) 38.Schwartz al.Perturbation writers classes sites.Cell Rep. 8: 284-296Abstract (558) 39.Liu METTL3–METTL14 methylation.Nat. 10: 93-95Crossref (1090) Then, discovery m6A-specific structural they conserved across species [40.Li F. al.Structure domain mononucleotide aromatic cage recognition.Cell 1490-1492Crossref (109) Scholar,41.Zhu al.Crystal structure recognition N6-methyladenosine.Cell 1493-1496Crossref (131) became characterize 2, Key Figure). Thus far, seems three YTHDF 3) can work together destabilize same subset [42.Lu W. al.N6-Methyladenosine-binding suppress HIV-1 infectivity production.J. 293: 12992-13005Crossref 43.Shi al.YTHDF3 facilitates N6-methyladenosine-modified RNA.Cell 315-328Crossref (500) 44.Tirumuru N. infection Gag expression.eLife. 5e15528Crossref (138) Nonetheless, outlining behind seem consistently indicate decay-inducing [45.Du al.YTHDF2 destabilizes direct recruitment CCR4–NOT complex.Nat. 12626Crossref (407) Scholar,46.Park O.H. al.Endoribonucleolytic RNase complex.Mol. 494-507.e498Abstract (126) Growing shows responsible localizing from translating pools bodies (P bodies) [47.Wang al.N6-Methyladenosine-dependent messenger 505: 117-120Crossref (1457) Scholar,48.Ries R.J. phase separation potential mRNA.Nature. 571: 424-428Crossref (171) where participating [49.Luo al.P-bodies: composition, properties, functions.Biochemistry. 57: 2424-2431Crossref (120) Scholar,50.Sheth U. Parker R. Decapping occur bodies.Science. 2003; 300: 805-808Crossref (914) study that, under stress conditions, partitions intracellular phase-separated compartments, P bodies, granules, granules [48.Ries However, another research group reported directly CCR4/NOT independently components, triggering precedes [51.Zheng al.Deadenylation prerequisite P-body cells.J. 2008; 182: 89-101Crossref Scholar] exosome (3′-to-5′ exoribonuclease complex), engaged deadenylation, 50.Sheth 51.Zheng CCR4/NOT-mediated subsequent exosome-mediated 3′-to-5′ exoribonucleolytic may initiate outside bodies. remaining intermediate then decapping, followed 5′-to-3′ decapping (XRN1) An additional route YTHDF2-mediated [46.Park bound associate P/MRP, endoribonuclease (Box bridged protein: heat-responsive 12 (HRSP12) reactive imine deaminase homolog, UK114 antigen 14.5 kDa translational inhibitor protein). Experiments based crosslinking immunoprecipitation next-generation sequencing characterized HRSP12 new RBP preference sequence GGUUC. Of note, located half palindromic sequence, suggesting recognize stem–loop primary sequences. Besides serving adaptor, mRNA. Moreover, With help binding, eventually performs Currently, remains unknown whether endoribonucleolytic-cleavage bodies.Box 1Molecular Properties P/MRPRNase MRP RNP complexes humans, yeast, mice, flies [86.Jarrous Roles subunits.Trends 33: 594-603Abstract (27) endonuclease cleaves leader precursor form tRNAs. subunits combinatorial assembly give rise myriad complexes. cleave mitochondrial (hence name), mitochondria widely nuclease 5.8S rRNA processing. share least seven (POP1, POP5, RPP20, RPP25, RPP30, RPP38, RPP40) similar secondary tertiary structures. Other distinguished their unique ncRNA components: RPPH1 RMRP RNA, respectively.Targets limited tRNA, include long ncRNAs accumulate particular location CLB2 promote cycle progression. addition, viperin cleaved Park al. cytoplasm internally them respectively. Targets P/M

Language: Английский

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Roles of circular RNAs in immune regulation and autoimmune diseases

Cell Death and Disease, Journal Year: 2019, Volume and Issue: 10(7)

Published: June 26, 2019

Abstract Circular RNAs (circRNAs), as a novel class of endogenously expressed non-coding (ncRNAs), have high stability and often present tissue-specific expression evolutionary conservation. Emerging evidence has suggested that circRNAs play an essential role in complex human pathologies. Notably, circRNAs, important gene modulators the immune system, are strongly associated with occurrence development autoimmune diseases. Here, we focus on roles cells regulation, highlighting their potential biomarkers biological functions diseases, such systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), primary biliary cholangitis (PBC), psoriasis, aiming at providing new insights into diagnosis therapy these

Language: Английский

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The circRNA circPTPRA suppresses epithelial-mesenchymal transitioning and metastasis of NSCLC cells by sponging miR-96-5p

EBioMedicine, Journal Year: 2019, Volume and Issue: 44, P. 182 - 193

Published: May 31, 2019

BackgroundNon-small cell lung carcinomas (NSCLC) are prevalent, lethal cancers with especially grim prospects due to late-stage detection and chemoresistance. Circular RNAs (circRNAs) non-coding that participate in tumor development. However, the role of circRNAs NSCLC is not well known. This study investigated one circRNA – circPTPRA– characterized its molecular mechanism action.MethodscircPTPRA expression was analyzed human tumors matched healthy tissue. We performed functional characterization lines a mouse xenograft model elucidate circPTPRA epithelial-mesenchymal transitioning (EMT). also assessed regulatory action on microRNA miR-96-5p target suppressor Ras association domain-containing protein 8 (RASSF8).FindingscircPTPRA significantly downregulated relative Lower levels correlated metastasis inferior survival outcomes patients. suppressed EMT reduced murine by sequestering upregulating RASSF8. Correlation analyses patient-derived specimens supported involvement circPTPRA/miR-96-5p/RASSF8/E-cadherin axis dysregulation progression.InterpretationcircPTPRA suppresses sponging miR-96-5p, which upregulates downstream The can be leveraged as potential treatment avenue NSCLC.FundThe Key research development projects Anhui Province (201904a0720079), Natural Science Foundation (1908085MH240), Graduate Innovation Program Bengbu Medical College (Byycx1843), National Tibet (XZ2017ZR-ZY033) Technology Project Shannan (SNKJYFJF2017-3) Academic Subsidy for Top Talents Universities 2019 (gxbjZD16)

Language: Английский

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Circular RNAs as Therapeutic Agents and Targets

Frontiers in Physiology, Journal Year: 2018, Volume and Issue: 9

Published: Oct. 9, 2018

It has recently been reported that thousands of covalently linked circular RNAs (circRNAs) are expressed from human genomes. circRNAs emerge during RNA splicing. circularized in a reaction termed "backsplicing", whereby the spliceosome fuses splice donor site downstream exon to acceptor an upstream exon. Although young field research, first studies indicate backsplicing is not erroneous spliceosome. Instead, produced cells with high cell-type specificity and can exert biologically meaningful specific functions. These observations finding stable against exonucleolytic decay raising question whether may be relevant as therapeutic agents targets. In this review, we start out short introduction into classification, biogenesis general molecular mechanisms circRNAs. We then describe reports, where manipulating circRNA abundance shown have value animal disease models vivo, focus on cardiovascular diseases (CVD). Starting existing approaches, outline particular challenges opportunities for future circRNA-based approaches exploit stability effector functions native end considerations which designer could engineered artificial RNAs.

Language: Английский

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circRNA-miRNA-mRNA regulatory network in human lung cancer: an update

Cancer Cell International, Journal Year: 2020, Volume and Issue: 20(1)

Published: May 19, 2020

Circular RNAs, as hopeful diagnosis markers and therapeutic molecules, have been studied, probed applied into several diseases, such cardiovascular systemic lupus erythematosus, leukemia, pulmonary tuberculosis, cancer especially. Recently, mounting evidence has supported that circRNAs play a key role in the tumorigenesis, progress, invasion metastasis lung cancer. Its special structure-3'-5' covalent loop-allow it to execute functions both normal eukaryotic cells cells. Our review summaries latest studies on characteristics biogenesis of circRNAs, highlight regulatory about miRNA sponge lung-cancer-related circRNAs. In addition, interaction circRNA-miRNA-mRNA network will also be elaborated detail this review. Therefore, can provide new idea or strategy for further development application clinical setting terms early-diagnosis better treatment.

Language: Английский

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Circular RNAs and gastrointestinal cancers: Epigenetic regulators with a prognostic and therapeutic role

Critical Reviews in Oncology/Hematology, Journal Year: 2019, Volume and Issue: 145, P. 102854 - 102854

Published: Dec. 20, 2019

Language: Английский

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circRNAs and Exosomes: A Mysterious Frontier for Human Cancer

Molecular Therapy — Nucleic Acids, Journal Year: 2019, Volume and Issue: 19, P. 384 - 392

Published: Nov. 29, 2019

Exosomes are nano-sized membrane-bound vesicles and contain active substances (DNA, noncoding RNA [ncRNA], protein), which provide a novel method of transferring effector messages between cells. Circular RNAs (circRNAs), kind ncRNA, have attracted increasing attention over the last decade given advances in whole-genome transcriptome sequencing technologies. It has become increasingly clear that circRNAs regulate gene expression through various actions play diverse roles many fields human cancer biology. Notably, several studies reported enriched exosomes exosomal an important role Exosomal can be taken up by neighboring or distant cells affect aspects physiological pathological conditions recipient cells, potentially promoting cell communication tumor metastasis. Herein, we briefly review molecular mechanisms recent findings regarding circRNAs, highlight specific cancer.

Language: Английский

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