Emerging Epigenetic Regulation of Circular RNAs in Human Cancer

Molecular Therapy — Nucleic Acids, Journal Year: 2019, Volume and Issue: 16, P. 589 - 596

Published: April 19, 2019

Circular RNAs (circRNAs) are novel members of the noncoding RNA family. Their characteristic covalent closed-loop structure endows circRNAs that much more stable than corresponding linear transcript. ubiquitous in eukaryotic cells, and their functions diverse include adsorbing microRNAs (miRNAs; acting as miRNA sponges), regulating transcription, interacting with RNA-binding proteins, translating deriving pseudogenes. Moreover, associated occurrence progression a variety cancers, new biomarkers for early diagnosis to evaluate curative effects patient prognosis. Here, this paper briefly describes characteristics circRNAs, it further concludes relationship between human cancer. Based on potential encoded family can be divided into two categories, coding RNAs; long RNA, riRNA, tRNA, nsRNA, microRNA (miRNA). In recent years, research has made great progress identification RNAs, which involved biological processes.1Wilusz J.E. Sharp P.A. Molecular biology. A circuitous route RNA.Science. 2013; 340: 440-441Crossref PubMed Scopus (384) Google Scholar, 2Zhao W. Ma X. Liu L. Chen Q. Z. Zhang S. Wang Li H. Wu J. SNHG20: vital lncRNA multiple cancers.J. Cell. Physiol. 2019; (Published online January 15, 2019)https://doi.org/10.1002/jcp.28143Crossref (47) Scholar have nearly 30 years history. They special class derived from back-splicing or exon skipping pre-mRNAs. Unlike do not 5-cap 3-poly(A) tails, produced by exons, downstream 3-splicing donor is connected reverse bond upstream 5-split acceptor.3Pieler T. Theunissen O. TFIIIA: nine fingers--three hands?.Trends Biochem. Sci. 1993; 18: 226-230Abstract Full Text PDF (39) due circular structure, they easily degraded exonucleases, thus having longer half-life. considered inert by-products abnormally spliced RNAs. With emergence high-throughput sequencing, an increasing number been found cells. Increasing evidence shows expression profiles carcinoid tissues different those normal tissues.4Shi P. Sun He B. Song Kong Xue Profiles differentially expressed esophageal breast cancer.Cancer Manag. Res. 2018; 10: 2207-2221Crossref (35) 5Cheng X.Y. Shen [Circular Lung Cancer Research: Biogenesis, Functions Roles].Zhongguo Fei Ai Za Zhi. 21: 50-56PubMed addition, reported participate cellular cancer-related physiological processes, including cancer initiation, progression, metastasis.6Qu Yang Gao Y. Shang R. Dou K. RNA: star RNAs.Cancer Lett. 2015; 365: 141-148Crossref (1222) Therefore, in-depth analysis should help clarify epigenetic level mechanisms. According differences genome constituent sequences, three categories: exon-derived intron-derived composed exons introns.7Ashwal-Fluss Meyer M. Pamudurti N.R. Ivanov A. Bartok Hanan Evantal N. Memczak Rajewsky Kadener circRNA biogenesis competes pre-mRNA splicing.Mol. 2014; 56: 55-66Abstract (1951) 8Kelly Greenman C. Cook P.R. Papantonis Exon Skipping Is Correlated Circularization.J. Mol. Biol. 427: 2414-2417Crossref (245) 9Chen I. C.Y. Chuang T.J. identification, function exonic RNAs.Wiley Interdiscip. Rev. RNA. 6: 563-579Crossref (281) Three models used illuminate possible formation circRNAs: lariat-driven circularization, intron pairing-driven protein-driven circularization (Figure 1). During (cassette-on), lariat still reserves skipped exon(s). circle when splicing occurs before decomposed debranching enzymes. Lariat-driven also known exon-skipping mechanism. The partially folds during causing 5′ site (donor site) approach attack 3′ (receptor intron, whereby formed folded region, while remaining form mRNA.10Jeck W.R. Sorrentino J.A. Slevin M.K. Burd C.E. Marzluff W.F. Sharpless N.E. abundant, conserved, ALU repeats.RNA. 19: 141-157Crossref (2826) 11Wilusz 360° view RNAs: From functions.Wiley 9: e1478Crossref (300) This mechanism most circRNAs. For example, Kelly et al.8Kelly umbilical vein endothelial cells stimulated tumor necrosis factor α growth β contained large circularization. Intron direct Reverse complementary sequences flanks introns mediate Flanking (especially Alu sequences) play crucial part perfectly matched promote circRNAs.12Rybak-Wolf Stottmeister Glažar Jens Pino Giusti Behm Ashwal-Fluss al.Circular Mammalian Brain Are Highly Abundant, Conserved, Dynamically Expressed.Mol. 58: 870-885Abstract (1484) 13Koh Pan Gawad Fan H.C. Kerchner G.A. Wyss-Coray Blumenfeld Y.J. El-Sayed Y.Y. Quake S.R. Noninvasive vivo monitoring tissue-specific global gene humans.Proc. Natl. Acad. USA. 111: 7361-7366Crossref (200) procedure, patterns according whether partial retained, namely, (EcircRNAs) coexist (EIciRNAs).14Bahn J.H. F. Chan T.M. Lin Kim Wong D.T. Xiao landscape microRNA, Piwi-interacting saliva.Clin. Chem. 61: 221-230Crossref (489) Hsa-circ-POLR2A typical circRNA.13Koh proteins (RBPs) shorten distance receptor binding flanks, promoting exons. Muscleblind protein quaking RBPs circMbl circQKI, respectively.15Lasda E. Parker diversity function.RNA. 20: 1829-1842Crossref (848) 16Ivanov Wyler Torti Porath H.T. Orejuela M.R. Piechotta Levanon E.Y. Landthaler Dieterich Analysis reveals hallmarks animals.Cell Rep. 170-177Abstract (673) role some There hypotheses first hypothesis crosses enzyme then cleaves at both ends crossed exon, (lariat);7Ashwal-Fluss therefore, generated splicing. single Another that, base-paired, exon's end tail head, spliceosome bound receptor, resulting introns, cyclized released circRNA.8Kelly Many EcircRNAs contain encode normally standard sites through copolymer Genome-wide sequencing (RNA-seq) data suggests abundant mammalian transcriptome, EcircRNA conserved evolutionary variation, revealing functions.10Jeck 12Rybak-Wolf 17Wilusz Unexpected outputs many protein-coding genes.RNA 2017; 14: 1007-1017Crossref (79) Specifically, indicated steady plasma13Koh saliva,14Bahn suggesting may diagnostic biomarkers. contrast EcircRNAs, (IciRNAs) 3′∼5′ head-to-tail junction regions differ stability, subcellular localization, abundance, preservation, function. IciRNAs circularized chain branchpoints 2′∼5′, degenerating branchpoint avoiding detachment degradation specific way; actually stabilized lariats.15Lasda synthesis requires important site: c-rich containing 11 nt near terminus, length 7 nt, base-rich GU RNA-splicing branch site.16Ivanov Approximately 20% EIciRNAs retain retention would make subclass unique retaining IciRNAs. Mainly located nucleus, interact U1 small nuclear ribonucleoprotein particle (snRNP) transcription parental genes. regulation expression, enhance genes cis emphasize transcriptional strategy RNA-RNA interaction (snRNA).17Wilusz 18Li Huang Bao Zhong G. Yu Hu Dai al.Exon-intron regulate nucleus.Nat. Struct. 22: 256-264Crossref (1852) closed highly resistant digestion; preliminarily purified identified following molecular biology methods.19Jeck Detecting characterizing RNAs.Nat. Biotechnol. 32: 453-461Crossref (1745) (1) Most exonuclease R, niacin phosphatase 5′-terminal exonuclease, retained. Then, circRNA-specific primers quantitative samples, determine quantify after treatment.19Jeck 20Suzuki Zuo M.Q. Malhotra Mayeda Characterization RNase R-digested source consists splicing.Nucleic Acids 2006; 34: e63Crossref (428) (2) no polar end, migration rate cross-linked gel slower Compared homologous nucleic acids fewer weakly gels slower. northern blot analysis.21Tabak H.F. Van der Horst Smit Winter A.J. Mul Groot Koerkamp M.J. Discrimination circles, interlocked circles lariats using two-dimensional polyacrylamide electrophoresis.Nucleic 1988; 16: 6597-6605Crossref (33) 22Suzuki Tsukahara R RNAs.Int. 15: 9331-9342Crossref (314) (3) Fluorescence situ hybridization localize level, interfering (siRNAs) antisense oligonucleotides interfere verify circRNAs.23Li al.Corrigendum: Exon-intron 24: 194Crossref (60) 24Zhang X.O. Xiang J.F. Yin Q.F. Xing Y.H. Zhu L.L. intronic RNAs.Mol. 51: 792-806Abstract (1529) traditional methods, combination bioinformatics provides shortcut discovery low abundance. back-splicing, RNA-seq algorithm extremely inefficient distinguishing structures. Researchers effectively improved strategies algorithms follows: assuming forms rearrangement, candidate sequence boundary was constructed compared data;25Salzman R.E. Olsen M.N. P.L. Brown P.O. Cell-type features expression.PLoS Genet. e1003777Crossref (1391) directly alignment algorithms; detected cDNA designing splice sequences.26Hoffmann Otto Doose Tanzer Langenberger D. Christ Kunz Holdt L.M. Teupser Hackermüller Stadler P.F. multi-split mapping splicing, trans-splicing fusion detection.Genome R34Crossref (180) At present, map-splice,27Li Diao Long non-coding HOXD-AS1 cancer.Clin. Chim. Acta. 487: 197-201Crossref (36) Circ Seq,10Jeck CIRI,28Gao Zhao CIRI: efficient unbiased de novo identification.Genome 4Crossref (670) explorer.29Zhang H.B. Lu Complementary sequence-mediated circularization.Cell. 159: 134-147Abstract CIRI annotation-related only detect transcribed intergenomic but applied annotated unannotated eukaryotes. Since lack poly(A) common oligomeric dT enrichment method ineffective. Ribo-Zero kit, eliminate rRNA remove enrich circRNAs.20Suzuki miRNAs sponges, selective RBPs, pseudogenes, transporting substances information. presented Figure 2. response element (MRE) binds prevents them target mRNAs.30Memczak Elefsinioti Krueger Rybak Maier Mackowiak S.D. Gregersen L.H. Munschauer animal regulatory potency.Nature. 495: 333-338Crossref (5161) 31Hansen T.B. Jensen T.I. Clausen B.H. Bramsen J.B. Finsen Damgaard C.K. Kjems Natural sponges.Nature. 384-388Crossref (5173) proof sponges cerebellar degeneration-related 1 (CDR1as) determined related its functions. CDR1as reduce brain volume hinder development fetal process zebrafish embryos, injection miR-7 restore development, indicating bind miR-7.31Hansen circHIPK3 2 HIPK3 silenced mRNA significantly inhibited Through luciferase screening, 9 18 specifically miR-124 inhibit activity. However, showed miRNA-binding necessarily strong spongy effect, other confirmed viewpoint.32Guo J.U. Agarwal V. Guo Bartel D.P. Expanded characterization RNAs.Genome 409Crossref (1134) 33You Vlatkovic Babic Will Epstein Tushev Akbalik Glock Quedenau al.Neural synaptic regulated plasticity.Nat. Neurosci. 603-610Crossref (743) act phenomenon remains explained. variable transcription. Variable pre-mRNAs isomers methods (different selected), circMBL, second MBL (muscleblind), pre-mRNA. side MBL-binding sites, strongly MBL. obviously influences cyclization circMbl, based flanks.6Qu 7Ashwal-Fluss translation initiation potentially compete host splices. mode balance levels mRNAs. production posttranscriptional level. c-sirt7 pol complex, leading decreased anchor repeat domain-52 deacetylase-7. EIciRNAs, mostly localized ribosome snRNP genes.18Li like perform functions.34Yin Y.W. Carmichael G.G. snoRNA ends.Mol. 2012; 48: 219-230Abstract (306) 35Li Fox A.H. SPArking Interest Noncoding World: New Class SnoRNA-Stabilized LncRNA Influences Alternative Splicing.Mol. 2016; 64: 435-437Abstract (6) When combined complexes, store them,7Ashwal-Fluss complexes. stably molecules As scaffold DNA provide platform DNA. action Ago2 hydrolysis.36Hansen Wiklund E.D. Villadsen S.B. Statham A.L. Clark S.J. miRNA-dependent silencing involving Ago2-mediated cleavage RNA.EMBO 2011; 30: 4414-4422Crossref (702) Du al.37Du W.W. Dhaliwal B.B. Foxo3 retards cell cycle via forming ternary complexes p21 CDK2.Nucleic 44: 2846-2858Crossref (1079) circ-foxo3 cyclin-dependent kinase (CDK2) inhibitor p21. Abdelmohsen al.38Abdelmohsen Panda A.C. Munk Grammatikakis Dudekula D.B. De Noh K.M. Martindale J.L. Gorospe Identification HuR uncovers suppression PABPN1 CircPABPN1.RNA 361-369Crossref (508) circ-PABPN1 could competitively RBP poly(A)-binding (PABPN1) mRNA, reducing mRNA. plays major cancer, proliferation one main By studying better understood, clues provided study tumorigenesis. species basically proteins. if internal entry point (IRES) inserted start codon functionally transcripts. previously shown vitro, engineered IRES, 40S subunit, IRES translation.39Wang Efficient backsplicing produces translatable mRNAs.RNA. 172-179Crossref (460) 40Thomas L.F. Sætrom depleted polymorphisms sites.Bioinformatics. 2243-2246Crossref (148) Similarly, Escherichia coli, open reading frames GFP transfected express GFP.39Wang al.41Du Yong Awan F.M. Identifying Characterizing circRNA-Protein Interaction.Theranostics. 7: 4183-4191Crossref (380) proved time modified m6A; is, methyl group added sixth base molecule, translation. Zhou al.42Zhou Molinie Daneshvar Pondick J.V. Wittenberghe Giallourakis C.C. Mullen Genome-Wide Maps m6A Identify Widespread Cell-Type-Specific Methylation Patterns Distinct mRNAs.Cell 2262-2276Abstract (249) modification specificity. Legnini al.43Legnini Di Timoteo Rossi Morlando Briganti Sthandier Fatica Santini Andronache Wade al.Circ-ZNF609 Can Be Translated Myogenesis.Mol. 66: 22-37.e9Abstract (1313) circ-ZNF609 muscle translate al.44Yang Yan al.Novel Role FBXW7 Repressing Glioma Tumorigenesis.J. Inst. 110: 304-315Crossref (681) circ-FBXW7 inhibits glioma, significance understanding glioma. Studies th

Language: Английский

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N6-methyladenosine METTL3 promotes the breast cancer progression via targeting Bcl-2

Gene, Journal Year: 2019, Volume and Issue: 722, P. 144076 - 144076

Published: Aug. 24, 2019

Language: Английский

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Splicing factor derived circular RNA circUHRF1 accelerates oral squamous cell carcinoma tumorigenesis via feedback loop

Cell Death and Differentiation, Journal Year: 2019, Volume and Issue: 27(3), P. 919 - 933

Published: Sept. 30, 2019

Language: Английский

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Circular RNA circSLC26A4 Accelerates Cervical Cancer Progression via miR-1287-5p/HOXA7 Axis

Molecular Therapy — Nucleic Acids, Journal Year: 2019, Volume and Issue: 19, P. 413 - 420

Published: Dec. 6, 2019

Circular RNAs (circRNAs) are group of noncoding derived from back-splicing events. Accumulating evidence certifies the critical roles circRNAs in human tumorigenesis. However, role and biogenesis cervical cancer still unclear. Here, a novel identified circRNA, circSLC26A4, was found to be upregulated tissue cells. Clinically, high expression circSLC26A4 related poor survival patients. Functionally, cellular experiments indicated that knockdown repressed proliferation, invasion, tumor growth vitro vivo. Furthermore, acted as sponge miR-1287-5p; moreover, miR-1287-5p targeted 3′ UTR HOXA7 mRNA. Mechanistically, RNA binding protein (RBP) quaking (QKI) interact with QKI response elements (QREs) SLC26A4 gene introns, thereby promoting biogenesis. In conclusion, these findings demonstrate facilitates progression through QKI/circSLC26A4/miR-1287-5p/HOXA7 axis, which might bring therapeutic strategies for cancer.

Language: Английский

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LncRNA CASC9 interacts with CPSF3 to regulate TGF-β signaling in colorectal cancer

Journal of Experimental & Clinical Cancer Research, Journal Year: 2019, Volume and Issue: 38(1)

Published: June 11, 2019

Colorectal cancer (CRC) is the third most frequent and second leading cause of cancer-related death worldwide. Increasing evidence indicates that deregulation long noncoding RNAs (lncRNAs) contributes to tumor initiation progression; however, little known about biological role susceptibility candidate 9 (CASC9) in CRC. Novel lncRNAs potentially involved CRC tumorigenesis were identified from datasets downloaded The Cancer LncRNome Atlas Noncoding Cancer. cell lines HCT-116, HCT-116 p53−/−, SW620, SW480, HT-29, LoVo, LS-174T, RKO used. Colony-formation, MTS, cell-cycle, apoptosis, in-vivo assays used determine CASC9 growth vitro vivo. Potential interaction between cleavage polyadenylation specificity factor subunit 3 (CPSF3) was evaluated using RNA immunoprecipitation RNA-protein pull-down assays. RNA-sequencing performed analyze gene expression following knockdown. RT-qPCR, western blotting, mRNA decay study mechanisms involved. frequently upregulated CRC, which correlated with advanced TNM stage, higher levels associated poor patient outcomes. Knockdown inhibited promoted apoptosis cells, whereas ectopic We demonstrated CPSF3 a CASC9-interacting protein, knockdown mimicked effects cells. Furthermore, we found exerts its oncogenic activity by modulating TGFβ2 stability upregulating TERT, resulting an increase phosphorylated SMAD3 activation TGF-β signaling, enhanced TERT complex function Finally, significantly tissues as compared adjacent or non-adjacent normal colon tissues, CASC9, CPSF3, human positively correlated. promising prognostic predictor for patients CASC9-CPSF3-TGFβ2 axis potential therapeutic target treatment.

Language: Английский

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circHECTD1 facilitates glutaminolysis to promote gastric cancer progression by targeting miR-1256 and activating β-catenin/c-Myc signaling

Cell Death and Disease, Journal Year: 2019, Volume and Issue: 10(8)

Published: Aug. 1, 2019

Abstract Circular RNAs (circRNAs) have emerged as crucial regulators of human cancers. Glutaminolysis supplies cancer cells with adequate nitrogen and carbon to replenish the tricarboxylic acid cycle, contributing survival progression tumor cells. However, association between circRNAs glutaminolysis remains unclear. In this study, we showed that circHECTD1 expression was markedly upregulated in gastric (GC) associated lymph node metastasis American Joint Committee on Cancer stage. The level found be an independent prognostic factor for GC patients. knockdown inhibited cell glutaminolysis, proliferation, migration, invasion, whereas overexpression promoted progression. Dual-luciferase RNA immunoprecipitation assays demonstrated miR-1256 a direct downstream target circHECTD1. targeted subsequently increased USP5. circHECTD1/miR-1256/USP5 axis exerted its tumor-promoting effects by activating β-catenin/c-Myc signaling pathway. vivo mouse models further verified oncogenic roles GC. Our results revealed is glutaminolysis-associated circRNA promotes could thus used therapeutic

Language: Английский

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LncRNA SNHG11 facilitates tumor metastasis by interacting with and stabilizing HIF-1α

Oncogene, Journal Year: 2020, Volume and Issue: 39(46), P. 7005 - 7018

Published: Oct. 15, 2020

Abstract Epigenetic alteration is one of the hallmarks colorectal cancer (CRC). Many driver genes are regulated by DNA methylation in CRC. However, role regulating lncRNAs remain elusive. Here, we identify that SNHG11 (small nucleolar RNA host gene 11) upregulated promotor hypomethylation CRC and associated with poor prognosis patients. can promote cell migration metastasis under hypoxia. Interestingly, DNA-binding motif similar to HIF-1α. In addition, SNHG11-associated enriched members HIF-1 signaling pathway Mechanistically, binds pVHLrecognition sites on HIF-1α, thus blocking interaction pVHL HIF-1α preventing its ubiquitination degradation. Moreover, upregulates expression target genes, i.e., AK4, ENO1, HK2, Twist1. Notably, bind HRE promoter these increase their transcription. summary, results a SNHG11/ axis plays pivotal tumor invasion metastasis.

Language: Английский

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Long non-coding RNA PSMA3-AS1 promotes malignant phenotypes of esophageal cancer by modulating the miR-101/EZH2 axis as a ceRNA

Aging, Journal Year: 2020, Volume and Issue: 12(2), P. 1843 - 1856

Published: Jan. 31, 2020

Emerging evidences has demonstrated that dysregulation of long non-coding RNAs (lncRNAs) is critically involved in esophageal squamous cell carcinoma (ESCC) progression. However, the function lncRNA PSMA3-AS1 ESCC unclear. Therefore, we aimed to explore functions and potential mechanisms cells progression.Here, found expression was significantly up-regulated tissues. Forced correlated with tumor size, distant metastasis, poor prognosis patients. Functionally, PSMA3-AS1-overexpression promoted proliferation, invasion, migration vitro. Mechanistically, EZH2 by competitively binding miR-101.PSMA3-AS1 tissues, PSMA3-AS1/miR-101/EZH2 axis plays a critical role Taken together, our results may provide promising targets for therapy.PSMA3-AS1 miR-101 were explored using qRT-PCR tissues lines. Immunohistochemistry assays carried out analyze (enhancer zeste homolog) protein expression. RIP, dual-luciferase reporter, fluorescence situ hybridization, biotin pull-down used detect interactions PSMA3-AS1, EZH2. The biological PSMA3-AS1-altered CCK-8, colony formation, wound healing, transwell

Language: Английский

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Circular RNA circSCAF11 Accelerates the Glioma Tumorigenesis through the miR-421/SP1/VEGFA Axis

Molecular Therapy — Nucleic Acids, Journal Year: 2019, Volume and Issue: 17, P. 669 - 677

Published: July 5, 2019

Circular RNAs (circRNAs) are a novel category of non-coding RNAs, and they have been identified to participate in glioma tumorigenesis. Here we investigated the functions circRNA circSCAF11 genesis, unveiled its molecular mechanism pathophysiological process. Expression levels circSCAF11, miR-421, SP1 mRNA were measured using RT-PCR. Proteins western blotting. The tumor phenotypes cells detected flow cytometry Cell Counting Kit-8 (CCK-8), transwell, xenograft mouse assays. combination within was validated luciferase reporter assay or RNA pull-down assay. binding transcription factor with vascular endothelial cell growth A (VEGFA) promoter inspected chromatin immunoprecipitation (ChIP). expression found be significantly upregulated tissue specimens lines. ectopic overexpression closely correlated poor clinical outcome patients. Functionally, knockdown inhibited proliferation, invasion, induced G0/G1 phase arrest. Mechanically, positively regulated through sponging miR-421. Moreover, activated VEGFA, constructing circSCAF11/miR-421/SP1/VEGFA axis genesis. findings this research illustrate that accelerates tumorigenesis miR-421/SP1/VEGFA axis, providing potential target for treatment.

Language: Английский

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SP1‐mediated lncRNA PVT1 modulates the proliferation and apoptosis of lens epithelial cells in diabetic cataract via miR‐214‐3p/MMP2 axis

Journal of Cellular and Molecular Medicine, Journal Year: 2019, Volume and Issue: 24(1), P. 554 - 561

Published: Nov. 21, 2019

Abstract Emerging evidence illustrates the critical roles of long non‐coding RNAs (lncRNAs) in diabetes. However, deepgoing regulation lncRNA PVT1 diabetic cataract (DC) is still unclear. Here, present research investigates pathologic and underlying mechanism by which regulates DC pathogenesis. Human lens epithelial (HLE) B‐3 cells were induced high glucose (HG) to simulate microenvironment models. Results revealed that expression was up‐regulated HG‐induced HLE as compared normal group. Transcription factor SP1 could bind with promoter region activate its transcription. Functionally, knock‐down repress proliferation promote apoptosis cells. Mechanistically, acted ‘miRNA sponge’ target miR‐214‐3p/MMP2 axis. This finding a novel insight for pathogenesis, providing an inspiration mechanism.

Language: Английский

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