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1.
Medicine (Baltimore) ; 100(14): e25415, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33832139

RESUMO

BACKGROUND: Circular RNAs (circRNAs) regulate multiple pathways during lung cancer pathogenesis. Apart from functional significance, many circRNAs have been shown to be associated with clinicopathological characteristics and predict lung cancer prognosis. Our aim is to summarize the expanding knowledge of clinical roles of circRNAs in lung cancer. METHODS: A thorough search of literature was conducted to identify articles about the correlation between circRNA expression and its prognostic and clinicopathological values. Biological mechanisms were summarized. RESULTS: This study included 35 original articles and 32 circRNAs with prognostic roles for lung cancer. Increased expression of 25 circRNAs and decreased expression of 7 circRNAs predicted poor prognosis. For non-small cell lung cancer, changes of circRNAs were correlated with tumor size, lymph node metastasis, distant metastasis, tumor node metastasis (TNM) stage, and differentiation, indicating the major function of circRNAs is to promote lung cancer invasion and migration. Particularly, meta-analysis of ciRS-7, hsa_circ_0020123, hsa_circ_0067934 showed increase of the 3 circRNAs was associated with positive lymph node metastasis. Increase of ciRS-7 and hsa_circ_0067934 was also related with advanced TNM stage. The biological effects depend on the general function of circRNA as microRNA sponge. CONCLUSIONS: CircRNAs have the potential to function as prognostic markers and are associated with lung cancer progression and metastasis.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias Pulmonares/diagnóstico , RNA Circular/metabolismo , Progressão da Doença , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico
3.
Molecules ; 26(4)2021 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-33670057

RESUMO

The prevention and diagnosis of sudden cardiac death (SCD) are among the most important keystones and challenges in clinical and forensic practice. However, the diagnostic value of the current biomarkers remains unresolved issues. Therefore, novel diagnostic biomarkers are urgently required to identify patients with early-stage cardiovascular diseases (CVD), and to assist in the postmortem diagnosis of SCD cases without typical cardiac damage. An increasing number of studies show that circular RNAs (circRNAs) have stable expressions in myocardial tissue, and their time- and tissue-specific expression levels might reflect the pathophysiological status of the heart, which makes them potential CVD biomarkers. In this article, we briefly introduced the biogenesis and functional characteristics of circRNAs. Moreover, we described the roles of circRNAs in multiple SCD-related diseases, including coronary artery disease (CAD), myocardial ischemia or infarction, arrhythmia, cardiomyopathy, and myocarditis, and discussed the application prospects and challenges of circRNAs as a novel biomarker in the clinical and forensic diagnosis of SCD.


Assuntos
Doença da Artéria Coronariana/diagnóstico , Morte Súbita Cardíaca/patologia , Medicina Legal , RNA Circular/sangue , Biomarcadores/sangue , Biomarcadores/metabolismo , Doença da Artéria Coronariana/sangue , Humanos , RNA Circular/genética , RNA Circular/metabolismo
4.
BMC Cancer ; 21(1): 277, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33722210

RESUMO

BACKGROUND: As one of the novel molecules, circRNA has been identified closely involved in the pathogenesis of many diseases. However, the function of circRNA in acute myeloid leukemia (AML) still remains unknown. METHODS: In the current study, the RNA expression profiles were obtained from Gene Expression Omnibus (GEO) datasets. The differentially expressed RNAs were identified using R software and the competing endogenous RNA (ceRNA) network was constructed using Cytoscape. Functional and pathway enrichment analyses were performed to identify the candidate circRNA-mediated aberrant signaling pathways. The hub genes were identified by MCODE and CytoHubba plugins of Cytoscape, and then a subnetwork regulatory module was established. RESULTS: A total of 27 circRNA-miRNA pairs and 208 miRNA-mRNA pairs, including 12 circRNAs, 24 miRNAs and 112 mRNAs were included in the ceRNA network. Subsequently, a subnetwork, including 4 circRNAs, 5 miRNAs and 6 mRNAs, was established based on related circRNA-miRNA-mRNA regulatory modules. CONCLUSIONS: In summary, this work analyzes the characteristics of circRNA as competing endogenous RNA in AML pathogenesis, which would provide hints for developing novel prognostic, diagnostic and therapeutic strategy for AML.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Leucemia Mieloide Aguda/genética , RNA Circular/metabolismo , Biomarcadores Tumorais/análise , Biologia Computacional , Conjuntos de Dados como Assunto , Perfilação da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , MicroRNAs/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas/genética , RNA Circular/análise , RNA Mensageiro/metabolismo , Transdução de Sinais/genética , Análise de Sobrevida
5.
BMC Cancer ; 21(1): 284, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33726686

RESUMO

BACKGROUND: Circular RNAs (circRNAs) feature prominently in tumor progression. However, the biological function and molecular mechanism of circ_0003266 in colorectal cancer (CRC) require further investigation. METHODS: Circ_0003266 expression in 46 pairs CRC tissues / adjacent tissues, and CRC cell lines was detected by quantitative real-time polymerase chain reaction (qRT-PCR); after circ_0003266 was overexpressed or knocked down in CRC cells, cell proliferation, apoptosis, migration, and invasion were evaluated by the cell counting kit-8 (CCK-8), flow cytometry, and Transwell assays, respectively; the interaction among circ_0003266, miR-503-5p, and programmed cell death 4 (PDCD4) was confirmed using bioinformatics analysis and dual-luciferase reporter assay; PDCD4 protein expression in CRC cells was quantified using Western blot. RESULTS: Circ_0003266 was significantly lowly expressed in CRC tissues and cell lines. Circ_0003266 overexpression markedly repressed CRC cell proliferation, migration, and invasion, and accelerated the cell apoptosis, but its overexpression promoted the malignant phenotypes of CRC cells. PDCD4 was a direct target of miR-503-5p and circ_0003266 promoted PDCD4 expression by competitively sponging miR-503-5p. CONCLUSION: Circ_0003266 suppresses the CRC progression via sponging miR-503-5p and regulating PDCD4 expressions, which suggests that circ_0003266 may serve as a novel target for the treatment of CRC.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/metabolismo , RNA Circular/metabolismo , Proteínas de Ligação a RNA/genética , Adulto , Linhagem Celular Tumoral , Neoplasias Colorretais/cirurgia , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Masculino , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , Pessoa de Meia-Idade , RNA Circular/genética , Adulto Jovem
6.
Life Sci ; 275: 119375, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33737085

RESUMO

AIMS: Both aerobic exercise and glucosamine hydrochloride capsules (OTL) have a therapeutic effect on knee osteoarthritis, but their joint application has not been investigated. This study clarified the mechanism of the combined treatment in knee osteoarthritis. MAIN METHODS: Aerobic exercise and OTL were used alone or in combination to treat papain-induced knee osteoarthritis model rabbits. Pathological changes of cartilage tissues, inflammatory cytokine content, glycosaminoglycan, and expressions of collagen II, cartilage differentiation-related genes and circUNK were analyzed by hematoxylin-eosin staining, Mankin score, Enzyme-linked immunosorbent assay, toluidine blue staining, Immunohistochemistry and qRT-PCR. The extracted chondrocytes were identified by Alcian Blue staining and immunohistochemistry and induced by iodoacetic acid (MIA) to establish osteoarthritis model. Effects of overexpressing or silencing circUNK on cell function and molecular changes in chondrocytes were analyzed by cell function experiments, qRT-PCR and Western blot. Rabbit modeling and intervention treatment were marked. KEY FINDINGS: Aerobic exercise or OTL treatment alone relieved the damage caused by knee osteoarthritis in terms of cartilage tissue lesions, Mankin score, inflammatory cytokine content, glycosaminoglycan, and expressions of collagen II, cartilage differentiation-related genes and circUNK. Combined application of aerobic exercise and OTL showed better synergistic treatment effects. Transfection of overexpressed circUNK could attenuate the MIA-induced effect on cell viability and apoptosis in chondrocytes by regulating genes related to differentiation and apoptosis. Aerobic exercise combined with glucosamine had a synergistic therapeutic effect on knee osteoarthritis. SIGNIFICANCE: Overexpressing circUNK protected osteoarthritis model cells by regulating cartilage differentiation- and apoptosis-related genes.


Assuntos
Glucosamina/uso terapêutico , Osteoartrite do Joelho/terapia , Condicionamento Físico Animal , RNA Circular/metabolismo , Animais , Western Blotting , Cartilagem Articular/patologia , Condrócitos/patologia , Terapia Combinada , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Osteoartrite do Joelho/patologia , Condicionamento Físico Animal/métodos , Coelhos , Reação em Cadeia da Polimerase em Tempo Real
7.
Nat Cell Biol ; 23(3): 278-291, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33664496

RESUMO

Activated EGFR signalling drives tumorigenicity in 50% of glioblastoma (GBM). However, EGFR-targeting therapy has proven ineffective in treating patients with GBM, indicating that there is redundant EGFR activation. Circular RNAs are covalently closed RNA transcripts that are involved in various physiological and pathological processes. Herein, we report an additional activation mechanism of EGFR signalling in GBM by an undescribed secretory E-cadherin protein variant (C-E-Cad) encoded by a circular E-cadherin (circ-E-Cad) RNA through multiple-round open reading frame translation. C-E-Cad is overexpressed in GBM and promotes glioma stem cell tumorigenicity. C-E-Cad activates EGFR independent of EGF through association with the EGFR CR2 domain using a unique 14-amino-acid carboxy terminus, thereby maintaining glioma stem cell tumorigenicity. Notably, inhibition of C-E-Cad markedly enhances the antitumour activity of therapeutic anti-EGFR strategies in GBM. Our results uncover a critical role of C-E-Cad in stimulating EGFR signalling and provide a promising approach for treating EGFR-driven GBM.


Assuntos
Antígenos CD/metabolismo , Neoplasias Encefálicas/enzimologia , Caderinas/metabolismo , Glioblastoma/enzimologia , RNA Circular/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Antígenos CD/genética , Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Caderinas/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos Nus , Invasividade Neoplásica , RNA Circular/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Int J Mol Sci ; 22(4)2021 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-33562358

RESUMO

Circular RNAs (circRNAs) are a large class of RNAs with regulatory functions within cells. We recently showed that circSMARCA5 is a tumor suppressor in glioblastoma multiforme (GBM) and acts as a decoy for Serine and Arginine Rich Splicing Factor 1 (SRSF1) through six predicted binding sites (BSs). Here we characterized RNA motifs functionally involved in the interaction between circSMARCA5 and SRSF1. Three different circSMARCA5 molecules (Mut1, Mut2, Mut3), each mutated in two predicted SRSF1 BSs at once, were obtained through PCR-based replacement of wild-type (WT) BS sequences and cloned in three independent pcDNA3 vectors. Mut1 significantly decreased its capability to interact with SRSF1 as compared to WT, based on the RNA immunoprecipitation assay. In silico analysis through the "Find Individual Motif Occurrences" (FIMO) algorithm showed GAUGAA as an experimentally validated SRSF1 binding motif significantly overrepresented within both predicted SRSF1 BSs mutated in Mut1 (q-value = 0.0011). U87MG and CAS-1, transfected with Mut1, significantly increased their migration with respect to controls transfected with WT, as revealed by the cell exclusion zone assay. Immortalized human brain microvascular endothelial cells (IM-HBMEC) exposed to conditioned medium (CM) harvested from U87MG and CAS-1 transfected with Mut1 significantly sprouted more than those treated with CM harvested from U87MG and CAS-1 transfected with WT, as shown by the tube formation assay. qRT-PCR showed that the intracellular pro- to anti-angiogenic Vascular Endothelial Growth Factor A (VEGFA) mRNA isoform ratio and the amount of total VEGFA mRNA secreted in CM significantly increased in Mut1-transfected CAS-1 as compared to controls transfected with WT. Our data suggest that GAUGAA is the RNA motif responsible for the interaction between circSMARCA5 and SRSF1 as well as for the circSMARCA5-mediated control of GBM cell migration and angiogenic potential.


Assuntos
Adenosina Trifosfatases/genética , Movimento Celular , Proteínas Cromossômicas não Histona/genética , Glioblastoma/irrigação sanguínea , Glioblastoma/patologia , Neovascularização Patológica/patologia , RNA Circular/metabolismo , Fatores de Processamento de Serina-Arginina/metabolismo , Apoptose , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Células Endoteliais/patologia , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Motivos de Nucleotídeos , Prognóstico , RNA Circular/genética , Fatores de Processamento de Serina-Arginina/genética , Células Tumorais Cultivadas
9.
Life Sci ; 272: 119233, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33600863

RESUMO

Aim Increasing evidence demonstrated circular RNAs (circRNAs) are involved in the development of various diseases, including sepsis-induced AKI. Although CIRC-Ttc3 has been proved to regulate cardiac function after myocardial infarction, its role in sepsis-induced AKI remains unclear. MATERIALS AND METHODS: The AKI rat model was firstly induced by sepsis through cecal ligation puncture (CLP). Serum levels of creatinine, BUN, NGAL, TNF-α, IL-6, SOD, MDA and IL-1ß were measured through appropriate kits. The pathological alteration and renal microvascular permeability in renal tissues were determined by HE staining and Evans Blue assays. Cell apoptosis was detected by TUNEL assay. The expression levels of CIRC-Ttc3, miR-148a, TNF-α, IL-1ß and iNOS in rats' renal samples were tested by qRT-PCR or/and western blot. The binding ability between CIRC-Ttc3 and miR-148a was evaluated through luciferase reporter, RIP and RNA pull-down assays. KEY FINDINGS: Kidney injury was found in CLP-treated rats. CIRC-Ttc3 expression was down-regulated, and upregulation of CIRC-Ttc3 improved inflammatory responses and oxidative stress in AKI rats. Mechanismly, CIRC-Ttc3 was confirmed to bind to and negatively regulate miR-148a. Further rescue assays revealed that overexpression of miR-148a rescued the improvement of CIRC-Ttc3 on sepsis-induced AKI. Then, it was illustrated that CIRC-Ttc3 regulated Rcan2 expression by binding to miR-148a. Finally, knockdown of Rcan2 reversed the effects of miR-148a inhibition on sepsis-induced AKI. SIGNIFICANCE: CIRC-Ttc3 relieved inflammation and oxidative stress through regulating the miR-148a/Rcan2 axis in rats with AKI induced by sepsis. Therefore, CIRC-Ttc3 may be a potential therapeutic target for sepsis-induced AKI.


Assuntos
Lesão Renal Aguda/genética , RNA Circular/genética , Lesão Renal Aguda/metabolismo , Animais , Apoptose/genética , China , Modelos Animais de Doenças , Inflamação/genética , Rim/metabolismo , Rim/patologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Estresse Oxidativo/genética , RNA Circular/metabolismo , RNA Longo não Codificante/genética , Ratos , Ratos Sprague-Dawley , Sepse/complicações , Sepse/genética , Fator de Necrose Tumoral alfa/metabolismo
10.
Mol Med Rep ; 23(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33537815

RESUMO

Dysregulated circular RNAs (circRNAs) are involved in the carcinogenesis and progression of multiple human malignancies. Knowledge of circRNAs in glioma (GM) is limited and further study to uncover new therapeutic targets for GM is urgently required. The present study demonstrated that circ­TOP2A was elevated in GM tissue specimens and cells and that circ­TOP2A levels indicated an unfavorable clinical prognosis in GM. Functionally, circ­TOP2A knockdown reduced viability, migration and invasion and triggered apoptosis in LN229 cells. Ectopic expression of circ­TOP2A aggravated these malignant behaviors in U87MG cells. In terms of mechanism, RNA­seq was performed to discover the potential targets regulated by circ­TOP2A. Circ­TOP2A acted as a competing endogenous RNA to upregulate sushi domain­containing 2 (SUSD2) expression by sponging microRNA (miR) 346. Rescue assays revealed that the oncogenic function of circ­TOP2A was partially dependent on its regulation of the miR­346/SUSD2 axis. In conclusion, the present study identified that circ­TOP2A promoted GM proliferation and aggressiveness via miR­346/SUSD2 signaling, which is a potential prognostic biomarker and therapeutic target for GM.


Assuntos
Apoptose , Movimento Celular , Glicoproteínas de Membrana/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/metabolismo , RNA Circular/metabolismo , RNA Neoplásico/metabolismo , Linhagem Celular Tumoral , Glioma , Humanos , Glicoproteínas de Membrana/genética , MicroRNAs/genética , Metástase Neoplásica , Proteínas de Neoplasias/genética , RNA Circular/genética , RNA Neoplásico/genética
11.
Int J Mol Sci ; 22(4)2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546109

RESUMO

Circular RNAs (circRNAs) constitute a large class of non-coding RNAs characterized by a covalently closed circular structure. They originate during mRNA maturation through a modification of the splicing process and, according to the included sequences, are classified as Exonic, Intronic, or Exonic-Intronic. CircRNAs can act by sequestering microRNAs, by regulating the activity of specific proteins, and/or by being translated in functional peptides. There is emerging evidence indicating that dysregulation of circRNA expression is associated with pathological conditions, including cancer, neurological disorders, cardiovascular diseases, and diabetes. The aim of this review is to provide a comprehensive and updated view of the most abundant circRNAs expressed in pancreatic islet cells, some of which originating from key genes controlling the differentiation and the activity of insulin-secreting cells or from diabetes susceptibility genes. We will particularly focus on the role of a group of circRNAs that contribute to the regulation of ß-cell functions and that display altered expression in the islets of rodent diabetes models and of type 2 diabetic patients. We will also provide an outlook of the unanswered questions regarding circRNA biology and discuss the potential role of circRNAs as biomarkers for ß-cell demise and diabetes development.


Assuntos
Células Secretoras de Insulina/fisiologia , RNA Circular/metabolismo , Diabetes Mellitus , Regulação da Expressão Gênica , Humanos , Células Secretoras de Insulina/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/fisiologia
12.
Exp Mol Pathol ; 119: 104617, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33535081

RESUMO

Circular RNAs (circRNAs) have been implicated in the pathological regulation of human diseases by acting as microRNA (miRNA) sponges to affect gene expression. CircRNA Fragile Mental Retardation 2 (circ_AFF2) was dysregulated in rheumatoid arthritis (RA), but little is known about its specific function and hidden molecular mechanism in RA. Circ_AFF2, miR-375 and TAK1-binding 2 (TAB2) expression levels were determined through the quantitative real-time polymerase chain reaction (qRT-PCR). Flow cytometry was performed to analyze cell cycle and apoptosis. Cell proliferation detection was conducted by 3-(4, 5-dimethylthiazol-2-y1)-2, 5-diphenyl tetrazolium bromide (MTT) assay. The protein levels were measured using western blot. Inflammatory response was evaluated by enzyme-linked immunosorbent assay (ELISA). RNA pull-down assay was used to select the miRNA target of circ_AFF2. The interaction between miR-375 and circ_AFF2 or TAB2 was analyzed using the dual-luciferase reporter assay. Contrasted to normal samples and fibroblast-like synoviocytes (FLS), circ_AFF2 expression was upregulated in RA blood samples and FLS-RA cells. Cell cycle, proliferation and inflammatory response were blocked while apoptosis was promoted in FLS-RA after the downregulation of circ_AFF2. In addition, circ_AFF2 could interact with miR-375 and the function of circ_AFF2 was achieved by sponging miR-375 in FLS-RA cells. Moreover, TAB2 was a target of miR-375 and miR-375 repressed RA progression by decreasing TAB2 expression in FLS-RA cells. More importantly, circ_AFF2 promoted the expression of TAB2 by targeting miR-375. These findings clarified that circ_AFF2 induced cell progression, inflammatory response in FLS-RA cells via the miR-375/TAB2 axis. Circ_AFF2 could be used as a biomarker in the diagnosis and treatment of RA.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Artrite Reumatoide/genética , Fibroblastos/patologia , Inflamação/genética , MicroRNAs/metabolismo , RNA Circular/metabolismo , Transdução de Sinais , Sinoviócitos/patologia , Apoptose/genética , Artrite Reumatoide/sangue , Artrite Reumatoide/patologia , Sequência de Bases , Ciclo Celular/genética , Linhagem Celular , Proliferação de Células/genética , Progressão da Doença , Regulação para Baixo/genética , Humanos , Inflamação/patologia , MicroRNAs/genética , RNA Circular/sangue , RNA Circular/genética , Regulação para Cima/genética
13.
Parasitol Res ; 120(2): 715-723, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33452589

RESUMO

Circular RNAs (circRNAs) are a large class of non-protein-coding transcripts that are involved in a diverse spectrum of regulatory mechanisms across a broad range of biological processes. To date, however, few studies on circRNAs have investigated their role in the biology of invertebrate parasites. The ectoparasitic mite Varroa destructor is perceived as the principal biotic threat towards global honey bee health. This parasite cannot be sustainably controlled partially due to the lack of knowledge about its basic molecular biology. In this paper, we unveil the circRNA profile of V. destructor for the first time and report the sources, distribution, and features of the identified circRNAs. Exonic, intronic, exon-intron, and intergenic circRNAs were discovered and exon-intron circRNAs were the most abundant within the largest spliced length. Three hundred and eighty-six (8.3%) circRNAs were predicted to possess translational potential. Eleven circRNAs, derived from six parental genes, exhibited strong bonds with miRNAs as sponges, suggesting an efficient post-transcriptional regulation. GO term and KEGG pathway enrichment analyses of the parental genes of the identified circRNAs showed that these non-coding RNAs were mainly engaged in protein processing, signal transduction, and various metabolism processes. To our knowledge, this is the first catalog of a circRNA profile of parasitiformes species, which reveals the prevalence of circRNAs in the parasite and provides biological insights for future genetic studies on this ubiquitous parasitic mite.


Assuntos
Abelhas/parasitologia , RNA Circular/metabolismo , Varroidae/genética , Animais , Regulação da Expressão Gênica , Interações Hospedeiro-Parasita , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética
14.
Mol Med Rep ; 23(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33398368

RESUMO

Radiation therapy, one of the major treatment options for cancer, can cause delayed heart damage. The circular RNA (circRNA) circFOXO3 (hsa_circ_0006404) is associated with cancer progression. However, the functions of circFOXO3 in radiation­induced cardiotoxicity remains unknown. The present study aimed to identify the functions of cirFOXO3 in radiation­induced cardiotoxicity. The present study established circFOXO3­knockdown (KD) or ­overexpressing (OE) cardiomyocytes. Functional assay results showed that KD of circFOXO3 in cardiomyocytes significantly increased DNA damage and apoptosis after radiation. By contrast, OE of circFOXO3 reduced DNA damage and apoptosis rates in response to radiation. Mechanistically, KD of circFOXO3 elevated the levels of Bax, caspase 3 and caspase 7, and decreased Bcl­2 expression, whereas OE of circFOXO3 decreased Bax, caspase 3 and caspase 7 expression, and increased Bcl­2 expression. Thus, the present study indicated that circFOXO3 protected cardiomyocytes from radiation­induced cardiotoxicity by reducing DNA damage and apoptosis. circFOXO3 may be a potential therapeutic target against radiation­induced cardiotoxicity.


Assuntos
Apoptose , Cardiotoxicidade/metabolismo , Dano ao DNA , Raios gama/efeitos adversos , Miócitos Cardíacos/metabolismo , RNA Circular/metabolismo , Lesões Experimentais por Radiação/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Cardiotoxicidade/genética , Cardiotoxicidade/patologia , Linhagem Celular , Humanos , Miócitos Cardíacos/patologia , Lesões Experimentais por Radiação/patologia
15.
Planta ; 253(2): 26, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33410920

RESUMO

MAIN CONCLUSION: Circular RNAs (circRNAs) identification, expression profiles, and construction of circRNA-parental gene relationships and circRNA-miRNA-mRNA ceRNA networks indicate that circRNAs are involved in flag leaf senescence of rice. Circular RNAs (circRNAs) are a class of 3'-5' head-to-tail covalently closed non-coding RNAs which have been proved to play important roles in various biological processes. However, no systematic identification of circRNAs associated with leaf senescence in rice has been studied. In this study, a genome-wide high-throughput sequencing analysis was performed using rice flag leaves developing from normal to senescence. Here, a total of 6612 circRNAs were identified, among which, 113 circRNAs were differentially expressed (DE) during the leaf senescence process. Moreover, 4601 (69.59%) circRNAs were derived from the exons or introns of their parental genes, while 2110 (71%) of the parental genes produced only one circRNA. The sequence alignment analysis showed that hundreds of rice circRNAs were conserved among different plant species. Gene Ontology (GO) enrichment analysis revealed that parental genes of DE circRNAs were enriched in many biological processes closely related to leaf senescence. Through weighted gene co-expression network analysis (WGCNA), six continuously down-expressed circRNAs, 18 continuously up-expressed circRNAs and 15 turn-point high-expressed circRNAs were considered to be highly associated with leaf senescence. Additionally, a total of 17 senescence-associated circRNAs were predicted to have parental genes, in which, regulations of three circRNAs to their parental genes were validated by qRT-PCR. The competing endogenous RNA (ceRNA) networks were also constructed. And a total of 11 senescence-associated circRNAs were predicted to act as miRNA sponges to regulate mRNAs, in which, regulation of two circRNAs to eight mRNAs was validated by qRT-PCR. It is discussed that senescence-associated circRNAs were involved in flag leaf senescence probably through mediating their parental genes and ceRNA networks, to participate in several well-studied senescence-associated processes, mainly including the processes of transcription, translation, and posttranslational modification (especially protein glycosylation), oxidation-reduction process, involvement of senescence-associated genes, hormone signaling pathway, proteolysis, and DNA damage repair. This study not only showed the systematic identification of circRNAs involved in leaf senescence of rice, but also laid a foundation for functional research on candidate circRNAs.


Assuntos
Envelhecimento , Oryza , Folhas de Planta , RNA Circular , Envelhecimento/genética , Ontologia Genética , MicroRNAs/metabolismo , Oryza/genética , Folhas de Planta/genética , RNA Circular/genética , RNA Circular/metabolismo , RNA Mensageiro/metabolismo
16.
Nucleic Acids Res ; 49(3): 1631-1646, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33444453

RESUMO

Mammalian circRNAs can influence different cellular processes by interacting with proteins and other nucleic acids. Here, we used ribonucleoprotein immunoprecipitation (RIP) analysis to identify systematically the circRNAs associated with the cancer-related protein AUF1. Among the circRNAs interacting with AUF1 in HeLa (human cervical carcinoma) cells, we focused on hsa_circ_0032434 (circPCNX), an abundant target of AUF1. Overexpression of circPCNX specifically interfered with the binding of AUF1 to p21 (CDKN1A) mRNA, thereby promoting p21 mRNA stability and elevating the production of p21, a major inhibitor of cell proliferation. Conversely, silencing circPCNX increased AUF1 binding to p21 mRNA, reducing p21 production and promoting cell division. Importantly, eliminating the AUF1-binding region of circPCNX abrogated the rise in p21 levels and rescued proliferation. Therefore, we propose that the interaction of circPCNX with AUF1 selectively prevents AUF1 binding to p21 mRNA, leading to enhanced p21 mRNA stability and p21 protein production, thereby suppressing cell growth.


Assuntos
Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Ribonucleoproteína Nuclear Heterogênea D0/metabolismo , RNA Circular/metabolismo , Regiões 3' não Traduzidas , Sítios de Ligação , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células HeLa , Humanos , RNA Circular/química , RNA Mensageiro/metabolismo
17.
BMC Bioinformatics ; 22(1): 19, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33413092

RESUMO

BACKGROUND: Circular RNAs (circRNAs) are widely expressed in cells and tissues and are involved in biological processes and human diseases. Recent studies have demonstrated that circRNAs can interact with RNA-binding proteins (RBPs), which is considered an important aspect for investigating the function of circRNAs. RESULTS: In this study, we design a slight variant of the capsule network, called circRB, to identify the sequence specificities of circRNAs binding to RBPs. In this model, the sequence features of circRNAs are extracted by convolution operations, and then, two dynamic routing algorithms in a capsule network are employed to discriminate between different binding sites by analysing the convolution features of binding sites. The experimental results show that the circRB method outperforms the existing computational methods. Afterwards, the trained models are applied to detect the sequence motifs on the seven circRNA-RBP bound sequence datasets and matched to known human RNA motifs. Some motifs on circular RNAs overlap with those on linear RNAs. Finally, we also predict binding sites on the reported full-length sequences of circRNAs interacting with RBPs, attempting to assist current studies. We hope that our model will contribute to better understanding the mechanisms of the interactions between RBPs and circRNAs. CONCLUSION: In view of the poor studies about the sequence specificities of circRNA-binding proteins, we designed a classification framework called circRB based on the capsule network. The results show that the circRB method is an effective method, and it achieves higher prediction accuracy than other methods.


Assuntos
Biologia Computacional/métodos , RNA Circular , Algoritmos , Sítios de Ligação , Humanos , RNA Circular/genética , RNA Circular/metabolismo , Proteínas de Ligação a RNA
18.
Nat Commun ; 12(1): 295, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436560

RESUMO

Circular RNAs (circRNA) are a class of covalently closed single-stranded RNAs that have been implicated in cancer progression. Here we identify circNDUFB2 to be downregulated in non-small cell lung cancer (NSCLC) tissues, and to negatively correlate with NSCLC malignant features. Elevated circNDUFB2 inhibits growth and metastasis of NSCLC cells. Mechanistically, circNDUFB2 functions as a scaffold to enhance the interaction between TRIM25 and IGF2BPs, a positive regulator of tumor progression and metastasis. This TRIM25/circNDUFB2/IGF2BPs ternary complex facilitates ubiquitination and degradation of IGF2BPs, with this effect enhanced by N6-methyladenosine (m6A) modification of circNDUFB2. Moreover, circNDUFB2 is also recognized by RIG-I to activate RIG-I-MAVS signaling cascades and recruit immune cells into the tumor microenvironment (TME). Our data thus provide evidences that circNDUFB2 participates in the degradation of IGF2BPs and activation of anti-tumor immunity during NSCLC progression via the modulation of both protein ubiquitination and degradation, as well as cellular immune responses.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Progressão da Doença , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , RNA Circular/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células , Proteína DEAD-box 58/metabolismo , Regulação para Baixo/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Metástase Neoplásica , Complexo de Endopeptidases do Proteassoma/metabolismo , Ligação Proteica , Estabilidade Proteica , Proteólise , RNA Circular/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
19.
Ecotoxicol Environ Saf ; 208: 111672, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33396004

RESUMO

Along with the increasing application of graphene quantum dots (GQDs) in the fields of biomedicine and neuroscience, it is important to assess the probably adverse effects of GQDs in the central nervous system (CNS) but their underlying toxic mechanisms is still unclear. In this study, we evaluate the molecular mechanisms associated with circular RNAs (circRNAs) of nitrogen-doped GQDs (N-GQDs) and amino-functionalized GQDs (A-GQDs) damaging the cell viability and cellular structure in microglia by an integrative analysis of RNA microarray. The differentially expressed circRNA (DEcircRNAs)-miRNA- differentially expressed mRNA (DEmRNAs) regulatory networks were conducted in BV2 microglial cells treated with 25 µg/mL N-GQDs, 100 µg/mL N-GQDs and 100 µg/mL A-GQDs. Based on that, the protein-coding genes in each ceRNA network were collected to do bio-functional analysis to evaluate signaling pathways that were indirectly mediated by circRNAs. Some pathways that could play indispensable roles in the neurotoxicity of N-GQDs or both two kinds of GQDs were found. Low-dosed N-GQDs exposure mainly induced inflammatory action in microglia, while high-dosed N-GQDs and A-GQDs exposure both affect olfactory transduction and GABAergic synapse. Meanwhile, several classical signaling pathways, including mTOR, ErbB and MAPK, could make diverse contributions to the neurotoxicity of both two kinds of GQDs. These circRNAs could be toxic biomarkers or protective targets in neurotoxicity of GQDs. More importantly, they emphasized the necessity of comprehensive analysis of latent molecular mechanisms through epigenetics approaches in biosafety assessment of graphene-based nanomaterials.


Assuntos
Redes Reguladoras de Genes/efeitos dos fármacos , Grafite/toxicidade , Microglia/efeitos dos fármacos , Pontos Quânticos/toxicidade , RNA Circular/efeitos dos fármacos , Animais , Biomarcadores , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Grafite/química , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , Microglia/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
J Cancer Res Clin Oncol ; 147(3): 703-712, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33386469

RESUMO

OBJECTIVE: The malignant transformation of normal bladder cells (SV-HUC-1) was induced by arsenite to explore the possible mechanism of circRNA-100284 influencing bladder cancer cell proliferation. METHODS: Normal bladder SV-HUC-1 cells were cultured with 2 µM arsenite to induce malignant transformation. After 0, 3, 6, 12, and 24 h of culture, the expression level of circRNA-100284 in cells was detected by quantitative real-time PCR. Western blotting assays were used to detect the expression levels of EZH2 and cyclin-D1 proteins in cells treated with different media. Cell cycle was analyzed by flow cytometry. In addition, through cell transfection and CCK-8 experiments, the effect and mechanism of circRNA-100284 targeting microRNA-217 on proliferation was determined. The interaction between HSP70 methylation and Aurora-B was determined by Western blotting and immunoprecipitation experiments. RESULTS: With prolonged contact time with arsenite, the expression level of circRNA-100284 in cells increased continuously (P < 0.05). Western blotting assays showed that the expression levels of EZH2 and cyclin-D1 proteins in arsenite-transformed cells increased. Flow cytometry and CCK-8 showed that circRNA-100284 accelerated cell cycle transition and cell proliferation through miR-217. Finally, after culturing human bladder cancer T24 cells, combined with immunoprecipitation and in vitro kinase experiments, it was found that K561- dimethyl HSP70 activated Aurora-B, thus promoting the proliferation of bladder cancer cells. CONCLUSION: CircRNA-100284 activates aurora kinase B by inducing methylation of HSP70 via microRNA-217 to promote the proliferation of bladder cancer cells.


Assuntos
Aurora Quinase B/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , MicroRNAs/metabolismo , RNA Circular/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Animais , Arsenitos/farmacologia , Aurora Quinase B/genética , Ciclo Celular/fisiologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Transformação Celular Neoplásica/induzido quimicamente , Ciclina D2/genética , Ciclina D2/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Ativação Enzimática , Feminino , Proteínas de Choque Térmico HSP70/genética , Xenoenxertos , Humanos , Metilação , Camundongos , MicroRNAs/genética , RNA Circular/genética , Regulação para Cima , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
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