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1.
Medicine (Baltimore) ; 100(39): e27404, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596168

RESUMO

ABSTRACT: Cervical cancer (CC) is the third most common cancer among women and has a high mortality rate at the advanced stage. The mechanisms underlying the development and progression of CC are still elusive. Circular RNAs (circRNAs) play an important role in various physiological and pathological processes. The aim of this study was to identify the circRNAs significantly associated with cervical squamous cell carcinoma (CSCC), in order to discover novel diagnostic markers and elucidate their mechanistic basis.The circRNA expression profiles of CSCC and paired para-cancerous cervical tissues was downloaded from the Gene Expression Omnibus. Bioinformatics analysis were used to screen for the differentially expressed circRNAs (DECRs). The expression levels of hsa_circ_0000745, hsa_circ_0084927, hsa_circ_0002762, hsa_circ_0075341, hsa_circ_0007905, hsa_circ_0031027, hsa_circ_0065898, hsa_circ_0070190, and hsa_circ_0078383 were verified in CC and normal cervical tissues by quantitative real-time PCR.A total of 197 DECRs were identified between the CSCC and normal tissues, including 87 upregulated and 110 downregulated circRNAs. In addition, 37 miRNAs were predicted for the upregulated circRNAs and 39 for the downregulated circRNAs. Functional analysis showed that the DECRs were associated with positive regulation of substrate adhesion-dependent cell spreading, metabolism, positive regulation of GTPase activity, protein regulation, and intercellular adhesion. The MAPK signaling pathway that plays a significant role in the progression of CC, was also enriched. Consistent with the in-silico analysis, hsa_circ_0000745, hsa_circ_0084927, hsa_circ_0002762, hsa_circ_0007905 were upregulated and hsa_circ_0078383 was downregulated in CC tissues (P < .001), whereas hsa_circ_0075341 (P < .001) and hsa_circ_0031027 (P = .001) showed opposite trends.We identified novel diagnostic and therapeutic biomarkers of CSCC along with the mechanistic basis.


Assuntos
Carcinoma de Células Escamosas/genética , MicroRNAs/metabolismo , RNA Circular/metabolismo , Neoplasias do Colo do Útero/genética , Biomarcadores/metabolismo , Regulação para Baixo , Feminino , Humanos , Reação em Cadeia da Polimerase em Tempo Real , Regulação para Cima
2.
Anal Chim Acta ; 1183: 338966, 2021 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-34627513

RESUMO

CircRNA is a type of covalently closed circular RNA molecule that serves as a potential biomarker for the disease early diagnosis and clinical researches. To achieve living cell imaging of specific circRNA, we developed a novel graphene oxide (GO)-based catalytic hairpin assembly (CHA) and hybridization chain reaction (HCR) signal dual amplification system (GO-CHA-HCR, abbreviated GO-AR) for circ-Foxo3 imaging in living cells. The developed system consists of four types of designed hairpin DNA HP1, HP2, H1, and fluorophore-labeled H2, which are absorbed on the GO nanosheets surface leading to fluorescence quenching. In the presence of circ-Foxo3, the CHA cycle was initiated to form a hybrid chain with split fragments, which triggered the HCR cycle to generate dsDNA nanowires that were then released from GO. This process recovered the quenched fluorescence, realizing two-stage signal amplification. The GO-AR system effectively improved the signal-to-noise ratio compared to the traditional GO-CHA and GO-HCR detection system. The detection limit of circ-Foxo3 was as low as 15 pM with excellent sensitivity and selectivity. In addition, the enzyme-free sensing system was successfully applied in living cell circRNA imaging and serum circRNA detection, indicating its high potential in clinical diagnostics.


Assuntos
Grafite , RNA Circular , DNA/genética , Hibridização de Ácido Nucleico
3.
World J Gastroenterol ; 27(36): 6064-6078, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34629820

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer-related death worldwide. The 5-year survival rate of patients with early-stage CRC could reach 90%, but it is very low in patients with advanced-stage CRC. Recent studies have shown that circular RNAs play important roles in regulating the migration and invasion of CRC cells. AIM: To elucidate the role of circRNA_0084927 (circ_0084927) in the migration and invasion of CRC cells and its underlying mechanism. METHODS: Clinical tissue samples and cells were collected, and the expression of circ_0084927 was detected by quantitative polymerase chain reaction (qPCR). The diagnostic performance of circ_0084927 was assessed by receiver operating characteristic curve analysis. The role of circ_0084927 in CRC cell proliferation, migration, and invasion was determined using cell counting kit-8 assay, wound healing assay, and transwell assay, respectively. The regulatory relationship among circ_0084927, miRNA-20b-3p (miR-20b-3p), and glutathione S-transferase mu 5 (GSTM5) was identified using databases, luciferase reporter assay, qPCR, and Western blot analysis. AKT-mTOR signaling was also verified after circ_0084927 knockdown or miR-20b-3p mimic treatment. RESULTS: The expression of circ_0084927 was significantly increased in CRC tissues and cells, and it was higher in advanced-stage CRC compared with early-stage CRC. The area under the curve (AUC) of circ_0084927 was 0.806 [95% confidence interval (CI): 0.683-0.896]. In addition, the AUC was 0.874 (95%CI: 0.738-0.956) in patients with advanced-stage CRC and 0.713 (95%CI: 0.555-0.840) in those with early-stage CRC. Knockdown of circ_0084927 inhibited the migration and invasion of HCT116 cells. Moreover, circ_0084927 was found to act as a sponge of miR-20b-3p. MiR-20b-3p activation reduced the circ_0084927 level, whereas miR-20b-3p inhibition increased the circ_0084927 level. But the effect was not found after circ_0084927 mutation. In addition, miR-20b-3p expression in CRC patients was also reduced and negatively correlated with circ_0084927 expression. The function of circ_0084927 in HCT116 cells with circ_0084927 knockdown was rescued by miR-20b-3p. Moreover, GSTM5 expression was significantly decreased after overexpressing miR-20b-3p or inhibiting circ_0084927, but its expression was rescued when circ_0084927 and miR-20b-3p were both inhibited. Finally, AKT-mTOR signaling was markedly regulated by circ_0084927 and miR-20b-3p. CONCLUSION: The expression of circ_0084927 is significantly increased in CRC and higher in advanced-stage CRC than in early-stage CRC. Moreover, circ_0084927 potentially regulates CRC cell migration and invasion via the miR-20b-3p/GSTM5/ AKT/mTOR pathway.


Assuntos
Neoplasias Colorretais , MicroRNAs , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Glutationa Transferase , Humanos , MicroRNAs/genética , RNA Circular
4.
Medicine (Baltimore) ; 100(39): e27352, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34596142

RESUMO

INTRODUCTION: Recent studies have reported a connection between non-coding RNAs such as circular RNAs (circRNAs) and the prognosis of various cancers. However, the mechanism of circRNA in ovarian cancer and cervical cancer has not been consistent. We evaluated the diagnostic and prognostic roles of circRNAs in ovarian and cervical cancer by meta-analysis. METHODS: Pooled hazard ratios with 95% confidence intervals were to estimate overall survival. Diagnostic efficacy was estimated by sensitivity, specificity and area under curve. RESULTS: By searching PubMed, Embase, the Web of Science databases, and other sources, we obtained a total of 22 studies with 2059 patients from Asia population. High expression levels of oncogenic circRNAs were significantly associated with poor prognoses both in ovarian and cervical cancer. However, elevated expression levels of tumor-suppressor circRNAs were linked with favorable survival time in ovarian cancer. As for diagnostic role, the area under the curve value in ovarian cancer and cervical cancer is 0.89 and 0.93, respectively. CONCLUSIONS: CircRNAs have the prospect of becoming a promising biomarker for diagnosis and prognosis of ovarian and cervical cancer. Accordingly, circRNAs might be novel indicators and targets of therapy for ovarian and cervical cancer.


Assuntos
Neoplasias Ovarianas/epidemiologia , RNA Circular/biossíntese , Neoplasias do Colo do Útero/epidemiologia , Biomarcadores Tumorais , Feminino , Humanos , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/mortalidade , RNA Circular/sangue , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/mortalidade
5.
World J Surg Oncol ; 19(1): 265, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479583

RESUMO

INTRODUCTION: Colorectal cancer (CRC) is one of the most frequent neoplasms in the world. Based on the emerging role of noncoding RNAs, particularly circular RNAs in pathogenesis of cancers, we designed this study to inspect the expression levels of a circ0009910-mediated regulatory pathway in colorectal cancer. METHODS: After bioinformatics analyses and construction of putative circ0009910/ miR-145-5p/PEAK1 pathway, the expression levels of these components were evaluated in 50 CRC tissues and adjacent specimens by quantitative real-time PCR. Moreover, we appraised the correlation coefficients between these transcripts and calculated the correlation between circ0009910 expression levels with clinicopathological features of patients. RESULTS: Circ0009910 and PEAK1 were significantly upregulated, while miR-145-5p was decreased in CRC samples compared with adjacent tissues (p < 0.05). Moreover, statistically significant correlations were observed between expression levels of circ0009910, miR-145-5p, and PEAK1. We also reported considerable correlations between circ0009910 expression and clinicopathological parameters including sex and perineural invasion. Finally, ROC curve analysis showed circ0009910 level as a discriminative biomarker for CRC. CONCLUSION: For the first time, we could introduce circ0009910 as an important biomarker in CRC. Collectively, this investigation helped us to identify a newly diagnosed pathway in CRC that can be a potential axis for designing effective drugs for treatment of CRC patients.


Assuntos
Neoplasias Colorretais , MicroRNAs , Proteínas Tirosina Quinases/metabolismo , RNA Circular/genética , Proliferação de Células , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Prognóstico
6.
World J Surg Oncol ; 19(1): 268, 2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479589

RESUMO

BACKGROUND: Circular RNA 0029803 (circ_0029803) was found to be upregulated in colorectal cancer (CRC) tissues, but its function and underlying molecular mechanism are not studied in CRC. METHODS: The expression levels of circ_0029803, microRNA-216b-5p (miR-216b-5p), and ski-oncogene-like (SKIL) were measured by quantitative real-time polymerase chain reaction (qRT-PCR). RNase R treatment was used to affirm the existence of circ_0029803. Cell proliferation, apoptosis, migration, and invasion were assessed by colony formation, flow cytometry, and Transwell assays, respectively. A glucose and lactate assay kit was used to detect glucose consumption and lactate production. Western blot was applied to analyze the levels of all proteins. Dual-luciferase reporter assay was performed to assess the relationship between miR-216b-5p and circ_0029803 or SKIL. Tumor xenograft models were established to elucidate the effect of circ_0029803 in vivo. RESULTS: Circ_0029803 expression was enhanced in CRC tissues and cells, and the 5-year overall survival rate of patients with high circ_0029803 expression was substantially reduced. Circ_0029803 depletion retarded proliferation, migration, invasion, EMT and glycolysis of CRC cells in vitro as well as the tumor growth in vivo. Mechanically, circ_0029803 could serve as miR-216b-5p sponge to regulate its expression, and miR-216b-5p knockdown reversed the inhibition of si-circ_0029803 on the malignant behaviors of CRC cells. Additionally, as the target mRNA of miR-216b-5p, SKIL could counteract the inhibitory effect of miR-216b-5p on the development of CRC cells. Importantly, silencing circ_0029803 reduced SKIL expression via sponging miR-216b-5p. CONCLUSION: Circ_0029803 knockdown hindered proliferation, migration, invasion, EMT, and glycolysis and promoted apoptosis in CRC cells by modulating the miR-216b-5p/SKIL axis.


Assuntos
Neoplasias Colorretais , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs , RNA Circular , Animais , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , Prognóstico , Proteínas Proto-Oncogênicas , RNA Circular/genética
7.
J Transl Med ; 19(1): 389, 2021 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-34507559

RESUMO

BACKGROUND: Lung adenocarcinoma (LUAD) is a common subtype of lung cancer with high recurrence rate and fatality. Circ_0001361 has been recognized as key regulators in various malignancies, but its roles in LUAD remain ambiguous. METHODS: Circ_0001361, miR-525-5p, and VMA21 levels were assessed by RT-qPCR. The growth and metastasis of LUAD cells were detected by MTT, colony formation, wound scratch, and transwell assays, respectively. The interaction between circ_0001361/VMA21 and miR-525-5p was detected by dual luciferase, RNA immunoprecipitation, and RNA pull-down assays. VMA21 protein level was detected by Western blotting. Nude mouse xenograft model was established to determine the role of circ_0001361 in tumor growth in vivo. RESULTS: Circ_0001361 was up-regulated, while miR-525-5p was down-regulated in LUAD tissues and cells. Functional experiments demonstrated that circ_0001361 drove LUAD cell growth and metastasis. Mechanistically, circ_0001361 functioned as a sponge of miR-525-5p to up-regulate downstream target VMA21 level. MiR-525-5p/VMA21 axis was involved in circ_0001361-mediated malignant phenotypes of LUAD cells. Finally, inhibition of circ_0001361 restrained in vivo xenograft tumor growth via regulating miR-525-5p/VMA21 axis. CONCLUSION: Our findings elucidate that circ_0001361 facilitates the tumorigenesis and development of LUAD through miR-525-5p/VMA21 axis, providing evidence for circ_0001361 as a potential prognosis biomarker and therapeutic target for clinical treatment of LUAD.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , MicroRNAs/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , Adenocarcinoma de Pulmão/genética , Animais , Humanos , Neoplasias Pulmonares/genética , Camundongos , MicroRNAs/genética , Recidiva Local de Neoplasia , RNA Circular , ATPases Vacuolares Próton-Translocadoras/genética
8.
Biochemistry (Mosc) ; 86(9): 1060-1094, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34565312

RESUMO

Viruses exploit the translation machinery of an infected cell to synthesize their proteins. Therefore, viral mRNAs have to compete for ribosomes and translation factors with cellular mRNAs. To succeed, eukaryotic viruses adopt multiple strategies. One is to circumvent the need for m7G-cap through alternative instruments for ribosome recruitment. These include internal ribosome entry sites (IRESs), which make translation independent of the free 5' end, or cap-independent translational enhancers (CITEs), which promote initiation at the uncapped 5' end, even if located in 3' untranslated regions (3' UTRs). Even if a virus uses the canonical cap-dependent ribosome recruitment, it can still perturb conventional ribosomal scanning and start codon selection. The pressure for genome compression often gives rise to internal and overlapping open reading frames. Their translation is initiated through specific mechanisms, such as leaky scanning, 43S sliding, shunting, or coupled termination-reinitiation. Deviations from the canonical initiation reduce the dependence of viral mRNAs on translation initiation factors, thereby providing resistance to antiviral mechanisms and cellular stress responses. Moreover, viruses can gain advantage in a competition for the translational machinery by inactivating individual translational factors and/or replacing them with viral counterparts. Certain viruses even create specialized intracellular "translation factories", which spatially isolate the sites of their protein synthesis from cellular antiviral systems, and increase availability of translational components. However, these virus-specific mechanisms may become the Achilles' heel of a viral life cycle. Thus, better understanding of the unconventional mechanisms of viral mRNA translation initiation provides valuable insight for developing new approaches to antiviral therapy.


Assuntos
Células Eucarióticas/virologia , Iniciação Traducional da Cadeia Peptídica/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , Animais , Células Eucarióticas/fisiologia , Humanos , Sítios Internos de Entrada Ribossomal/fisiologia , RNA Circular/genética , Proteínas Virais/fisiologia
9.
Biomed Res Int ; 2021: 2628824, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34471635

RESUMO

Objective: This study is aimed at identifying key genes involved in neurological damage in preterm infants and at determining their potential circRNA-miRNA-mRNA regulatory mechanisms. Methods: Differentially expressed miRNAs, mRNAs, and circRNAs were downloaded from the GEO database. GO and KEGG enrichment analyses were used to determine possible relevant functions of differentially expressed mRNAs. The TTRUST database was used to predict differential TF-mRNA regulatory relationships. Then, CircMIR, miRDB, TargetScan and miRTarBase were then used to map circRNA/miRNA-TF/mRNA interaction networks. Finally, GSEA enrichment analysis was performed on the core transcription factors. Results: A total of 640 mRNAs, 139 circRNAs, and 206 differentially expressed miRNAs associated with neurological injury in preterm infants were obtained. Based on the findings of Cytoscape and PPI network analysis, the hsa_circ_0008439-hsa-mir-3665-STAT3-MMP3 regulatory axis was established. GSEA analysis revealed that suppressed expression levels of STAT3 were associated with upregulated oxidative phosphorylation pathways in the neurological injury group of preterm infants. Conclusions: The circRNA-miRNA-TF-mRNA regulatory network of neurological injury in preterm infants can be used to elucidate on the pathogenesis of brain injury and help us with the early detection of brain injury in preterm infants.


Assuntos
Recém-Nascido Prematuro , Metaloproteinase 3 da Matriz/metabolismo , MicroRNAs/genética , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , RNA Circular/genética , RNA Mensageiro/genética , Fator de Transcrição STAT3/metabolismo , Biologia Computacional/métodos , Bases de Dados Genéticas , Humanos , Recém-Nascido , Metaloproteinase 3 da Matriz/genética , Doenças do Sistema Nervoso/patologia , Fator de Transcrição STAT3/genética
10.
Biomed Res Int ; 2021: 8231414, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34527744

RESUMO

Objective: Provide a reference to elucidate the mechanism of circRNAs regulating osteoarthritis (OA) and the clinical treatment. Methods: Herein, articles about circRNAs (hsa-circ) and osteoarthritis in the recent 5 years have been reviewed and the differential expression and regulatory effect of circRNAs in OA deduced. Based on these conclusions and Protein-Protein Interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of the acquired circRNAs, the potential functions and interactions of circRNAs in OA and the involved signaling pathways are discussed. Results: A total of 33 studies meeting the inclusion criteria were included in this study, and 27 circRNAs were upregulated and 8 circRNAs were downregulated in OA. A total of 31 circRNAs were finally included in the PPI, GO, and KEGG analyses. From PPI, 12 map nodes and 7 map edges were interrelated. VWF had the biggest node and edge size. From GO, VWF showed a majority of the functions. From KEGG, circRNAs are enriched in PI3K/AKT, human papillomavirus infection (HPI), and focal adhesion (FA) pathways, and VWF was involved in major pathways. Conclusion: We found that most articles about circRNAs regulating OA in the recent 5 years focused on the mechanism, especially the absorption effect of circ-miRNA as sponges in the recent 2 years, while most of the articles about their functions addressed ECM and PI3K, AKT, and mTOR signaling pathways. Future studies might focus on the functions of circRNAs, and circRNA VWF, with preferable functions, interactions, and involvement, can be used as a biological indicator to detect OA in clinical practice.


Assuntos
Osteoartrite/genética , RNA Circular/genética , RNA Circular/fisiologia , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Redes Reguladoras de Genes/genética , Humanos , MicroRNAs/genética , Osteoartrite/metabolismo , Osteoartrite/fisiopatologia , Mapas de Interação de Proteínas/genética , RNA Circular/metabolismo , RNA Mensageiro/genética
11.
Molecules ; 26(17)2021 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-34500547

RESUMO

Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder that heavily burdens healthcare systems worldwide. There is a significant requirement to understand the still unknown molecular mechanisms underlying AD. Current evidence shows that two of the major features of AD are transcriptome dysregulation and altered function of RNA binding proteins (RBPs), both of which lead to changes in the expression of different RNA species, including microRNAs (miRNAs), circular RNAs (circRNAs), long non-coding RNAs (lncRNAs), and messenger RNAs (mRNAs). In this review, we will conduct a comprehensive overview of how RNA dynamics are altered in AD and how this leads to the differential expression of both short and long RNA species. We will describe how RBP expression and function are altered in AD and how this impacts the expression of different RNA species. Furthermore, we will also show how changes in the abundance of specific RNA species are linked to the pathology of AD.


Assuntos
Doença de Alzheimer/genética , RNA/genética , Animais , Humanos , MicroRNAs/genética , RNA Circular/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Transcriptoma/genética
12.
Int Heart J ; 62(5): 1112-1123, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34544967

RESUMO

Doxorubicin (DOX) is a widely used anticancer drug, but its cardiotoxicity largely limits its clinical utilization. Circular RNA spindle and kinetochore-associated protein 3 (circ-SKA3) were found to be differentially expressed in heart failure patients. In this study, we investigated the role and mechanism of circ-SKA3 in DOX-induced cardiotoxicity.The quantitative real-time polymerase chain reaction and western blot assays were applied to measure the expression of circ-SKA3, microRNA (miR) -1303, and toll-like receptor 4 (TLR4). The viability and apoptosis of AC16 cells were analyzed using cell counting kit-8, flow cytometry, and western blot assays. The interaction between miR-1303 and circ-SKA3 or TLR4 was verified using dual-luciferase reporter and RNA immunoprecipitation assays. Exosomes were collected from culture media by the use of commercial kits and then qualified by transmission electron microscopy.The expression of circ-SKA3 and TLR4 was increased, whereas miR-1303 expression was decreased in DOX-treated AC16 cells. DOX treatment promoted cell apoptosis and inhibited cell viability in AC16 cells in vitro, which was partially reversed by circ-SKA3 knockdown, TLR4 silencing, or miR-1303 overexpression. Mechanistically, circ-SKA3 served as a sponge for miR-1303 to upregulate TLR4, which was confirmed to be a target of miR-1303. Additionally, circ-SKA3 contributed to DOX-induced cardiotoxicity through the miR-1303/TLR4 axis. Further studies suggested that circ-SKA3 was overexpressed in exosomes extracted from DOX-mediated AC16 cells, which could be internalized by surrounding untreated AC16 cells.Circ-SKA3 enhanced DOX-induced toxicity in AC16 cells through the miR-1303/TLR4 axis. Extracellular circ-SKA3 was packaged into exosomes, and exosomal circ-SKA3 could function as a mediator in intercellular communication between AC16 cells.


Assuntos
Proteínas de Ciclo Celular/genética , Doxorrubicina/toxicidade , Proteínas Associadas aos Microtúbulos/genética , Miócitos Cardíacos/efeitos dos fármacos , Inibidores da Topoisomerase II/toxicidade , Apoptose/efeitos dos fármacos , Cardiotoxicidade/genética , Proteínas de Ciclo Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Exossomos/genética , Insuficiência Cardíaca/genética , Humanos , MicroRNAs/genética , Microscopia Eletrônica de Transmissão/métodos , Proteínas Associadas aos Microtúbulos/efeitos dos fármacos , Miócitos Cardíacos/patologia , RNA Circular/genética , Receptor 4 Toll-Like/efeitos dos fármacos , Receptor 4 Toll-Like/genética , Transfecção/métodos , Regulação para Cima
13.
Biomed Res Int ; 2021: 6672899, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34513995

RESUMO

Background: Slow transit constipation (STC) is characterized by persistent, infrequent, or incomplete defecation. Systematic analyses of mRNA, lncRNA, and circRNA expression profiling in STC provide insights to understand the molecular mechanisms of STC pathogenesis. The present study is aimed at observing the interaction of mRNAs, lncRNAs, and circRNAs by RNA sequencing in vivo of STC. Methods: A rat model of STC was induced by loperamide. The expression profiles of both mRNAs and miRNAs were performed by RNA sequencing. Enrichment analyses of anomalous expressed mRNAs, lncRNAs, and circRNAs were performed in order to identify the related biological functions and pathologic pathways through the Gene Ontology (GO) database and Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results: In total, 26435 mRNAs, 5703 lncRNAs, and 7708 circRNAs differentially expressed were identified between the two groups. The analyses of GO and KEGG show that (1) upregulated genes were enriched in a positive regulation of GTPase activity, cell migration, and protein binding and lipid binding and (2) GO annotations revealed that most trans-target mRNAs are involved in the regulation process of immune signal together with the proliferation and differentiation of immune cells. Additionally, the protein-protein interaction (PPI) network of differentially expressed (DE) mRNAs was constructed. Interestingly, all of the core lncRNAs and their coexpression mRNAs in this network are downregulated. Moreover, downregulated circRNAs have a set of target mRNAs related to immunoreaction, which was consistent with the overall tendency. Conclusion: Our investigation enriches the STC transcriptome database and provides a preliminary exploration of novel candidate genes and avenues expression profiles in vivo. The dysregulation of mRNAs, lncRNAs, and circRNAs might contribute to the pathological processes during STC.


Assuntos
Constipação Intestinal/genética , Transcriptoma/genética , Animais , Diferenciação Celular/genética , Constipação Intestinal/patologia , Modelos Animais de Doenças , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Redes Reguladoras de Genes/genética , Loperamida/farmacologia , Masculino , MicroRNAs/genética , Mapas de Interação de Proteínas/genética , RNA Circular/genética , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Análise de Sequência de RNA/métodos
14.
Biomed Res Int ; 2021: 5575286, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34545330

RESUMO

Purpose: Circular RNA as a competitive endogenous RNA (ceRNA) plays a significant role in the pathogenesis and progression of breast cancer. In this study, a circular RNA-related ceRNA regulatory network was constructed, which provides new biomarkers and therapeutic targets for the treatment of breast cancer. Materials and methods. The expression profile datasets (GSE101123, GSE143564, GSE50428) of circRNAs, miRNAs, and mRNAs were downloaded from the GEO database, and then differentially expressed RNAs (DEcircRNAs, DEmiRNAs, DEmRNAs) were obtained through the CSCD, TargetScan, miRDB, and miRTarBase databases. CircRNA-miRNA pairs and miRNA-mRNA pairs were constructed. Finally, a ceRNA regulatory network was established. Downstream analysis of the ceRNA network included GO, KEGG analysis, survival analysis, sub-network construction, the BCIP, and qRT-PCR verification. Results: In total, 144 differentially expressed (DE) DEcircRNA, 221 DEmiRNA, and 1211 DEmRNA were obtained, and 96 circRNA-miRNA pairs and 139 miRNA-mRNA pairs were constructed by prediction. The ceRNA regulatory network (circRNA-miRNA-mRNA) was constructed, which included 42 circRNA, 36miRNA, and 78 mRNA. GO function annotation showed genes were mainly enriched in receptor activity activated by transforming growth factor beta (TGF-beta) and in the regulation of epithelial cell apoptosis. KEGG analysis showed genes were mainly enriched in the TGF-beta signaling, PI3K-Akt signaling, and Wnt signaling pathways. Four genes associated with survival and prognosis of breast cancer were obtained by survival analysis, the prognostic sub-network included 4 circRNA, 4 miRNA, and 4 mRNA. BCIP analysis and qRT-PCR verification confirmed that relative mRNA expression levels were consistent with those in the GEO database. Conclusion: A circRNA-related ceRNA regulatory network was constructed for breast cancer in this study and key genes affecting pathogenesis and progression were identified. These findings may help better understand and further explore the molecular mechanisms that affect the progression and pathogenesis of breast cancer.


Assuntos
Neoplasias da Mama/genética , RNA Circular/genética , Biologia Computacional/métodos , Bases de Dados Genéticas , Detecção Precoce de Câncer/métodos , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Humanos , Programas de Rastreamento , MicroRNAs/genética , Mapas de Interação de Proteínas/genética , RNA Circular/análise , RNA Mensageiro/genética , Transdução de Sinais/genética , Transcriptoma/genética
15.
Brain Inj ; 35(10): 1245-1253, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34495821

RESUMO

BACKGROUND: Cerebral ischemia-reperfusion (CIR) injury is a severe disease, which may cause serious dysfunction of the brain. Most circular RNAs (circRNAs) have been demonstrated to play a significant role in CIR injury. However, a novel circRNA, circ_0062166 (circ_BCL2L13) has not been investigated for CIR injury. Hence, we aim to disclose the role of circ_0062166 in CIR injury in this study. METHODS: Firstly, RT-qPCR was applied to examine the expression of circ_0062166 in oxygen-glucose deprivation and reoxygenation (OGD/R) cell model. Functional assays were conducted to detect the role of circ_0062166 in CIR injury. RNA pull down, RIP and luciferase reporter assays were implemented to probe into the regulatory mechanism of circ_0062166. RESULTS: Circ_0062166 was significantly up-regulated in neuro-2A (N2A) neuroblastoma cells following OGD/R. Functionally, the silencing of circ_0062166 inhibited cell proliferation and promoted cell apoptosis under OGD/R condition. From the perspective of mechanism, circ_0062166 functioned as a competing endogenous RNA (ceRNA) for microRNA-526b-5p (miR-526b-5p) and regulated BCL2 like 13 (BCL2L13). Eventually, the promoting role of the circ_0062166/miR-526b-5p/BCL2L13 axis in the CIR injury was verified. CONCLUSION: To sum up, the present study has demonstrated that circ_0062166/miR-526b-5p/BCL2L13 axis accelerated the progression of CIR injury, which might provide effective strategies for CIR injury therapy.


Assuntos
MicroRNAs , Traumatismo por Reperfusão , Apoptose/genética , Glucose , Humanos , MicroRNAs/genética , RNA Circular , Traumatismo por Reperfusão/genética
16.
Nat Commun ; 12(1): 4825, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376658

RESUMO

Circular RNA (circRNA) is a class of covalently joined non-coding RNAs with functional roles in a wide variety of cellular processes. Their composition shows extensive overlap with exons found in linear mRNAs making it difficult to delineate their composition using short-read RNA sequencing, particularly for long and multi-exonic circRNAs. Here, we use long-read nanopore sequencing of nicked circRNAs (circNick-LRS) and characterize a total of 18,266 and 39,623 circRNAs in human and mouse brain, respectively. We further develop an approach for targeted long-read sequencing of a panel of circRNAs (circPanel-LRS), eliminating the need for prior circRNA enrichment and find >30 circRNA isoforms on average per targeted locus. Our data show that circRNAs exhibit a large number of splicing events such as novel exons, intron retention and microexons that preferentially occur in circRNAs. We propose that altered exon usage in circRNAs may reflect resistance to nonsense-mediated decay in the absence of translation.


Assuntos
Encéfalo/metabolismo , Éxons/genética , Íntrons/genética , Sequenciamento por Nanoporos/métodos , RNA Circular/genética , Análise de Sequência de RNA/métodos , Animais , Expressão Gênica , Humanos , Masculino , Camundongos da Linhagem 129 , Isoformas de RNA/genética , Splicing de RNA , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
17.
Clin Lab ; 67(8)2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34383411

RESUMO

BACKGROUND: The mortality rate of lung adenocarcinoma ranks first worldwide, higher than gastric, colorectal, breast, and other cancers. The lack of effective and accurate diagnosis contributes to the patient's unfavorable prognosis with lung adenocarcinoma since most patients are diagnosed at a late stage. In the present study, we aimed to investigate five circRNAs correlated with lung adenocarcinoma and their clinical roles. METHODS: We collected 68 unpaired serum and tissue samples from patients with lung adenocarcinoma and healthy volunteers. At the next stage, quantitative real-time polymerase chain reaction (qRT-PCR) assays were conducted. Furthermore, we uncovered the correlation of their expressions with clinicopathological features and the diagnostic values. Finally, the 5-year survival rate and disease-free rate were analyzed using Kaplan-Meier methods. RESULTS: The results revealed that expression levels of hsa_circ_001010, hsa_circ-ZNF609 were significantly elevated while hsa_circ-CRIMI1, hsa_circ-EPB41L2, and hsa_circ_0072309 were lower in lung adenocarcinoma serum samples and tissues than those in healthy controls (p < 0.05). Meanwhile, hsa_circ_001010 and hsa_circ-ZNF609 were downregulated hsa_circ-CRIMI1, hsa_circ-EPB41L2, and hsa_circ_0072309 were elevated in A549 cells compared with BEAS-2B cells. Knockdown of hsa_circ-CRIMI1, hsa_circ-EPB41L2, or hsa_circ_0072309 and overexpressing of hsa_circ_001010 and hsa_circ-ZNF609 could promote A549 cell apoptosis but inhibits proliferation as well. Furthermore, receiver operating characteristic (ROC) assays demonstrated that the area under the curve (AUC) were as follows: hsa_circ_001010 (0.8512, 95% CI, 0.7872 - 0.9152; p < 0.0001), hsa_circ-ZNF609 (0.7876, 95% CI, 0.7101 - 0.8651; p < 0.0001), hsa_circ-CRIMI1 (0.6614, 95% CI, 0.5708 - 0.7521; p < 0.0001), hsa_circ-EPB41L2 (0.6851, 95% CI, 0.5960 - 0.7742; p = 0.0002), and hsa_circ_0072309 (0.7359, 95% CI, 0.6250 - 0.8199; p < 0.0001). Notably, higher expressions of hsa_circ_001010, hsa_circ-ZNF609, and lower expressions of hsa_circ-CRIMI1, hsa_circ-BGT2, hsa_circ-EPB41L2, and hsa_circ_0072309 were positively correlated with clin-ical stage, lymph node metastasis, and smoking. Last but not least, patients with higher expressions of hsa_ circ_001010, hsa_circ-ZNF609, and lower expressions of hsa_circ-CRIMI1, hsa_circ-EPB41L2, and hsa_circ_ 0072309 had significantly lower overall survival rates and disease-free rates as well. CONCLUSIONS: We concluded that the five circRNAs might have diagnostic and prognosis significance in lung ade-nocarcinoma. However, further functional studies are warranted to ascertain the biological mechanisms of these circRNAs in the occurrence and development of lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/diagnóstico , Adenocarcinoma de Pulmão/genética , Biomarcadores , Biomarcadores Tumorais/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Prognóstico , RNA Circular
18.
World J Surg Oncol ; 19(1): 259, 2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34461926

RESUMO

BACKGROUND: The aberrant expression of circular RNAs (circRNAs) plays vital roles in the advancement of human cancers, including gastric cancer (GC). In this study, the functions of circRNA ring finger protein 111 (circ-RNF111) in GC were investigated. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) assay was performed for the levels of circ-RNF111, microRNA-876-3p (miR-876-3p) and krueppel-like factor 12 (KLF12) mRNA. RNase R assay was conducted for the feature of circ-RNF111. Cell Counting Kit-8 (CCK-8) assay, colony formation assay, wound-healing assay, and transwell assay were applied for cell viability, colony formation, migration, and invasion, respectively. Flow cytometry analysis was used to analyze cell apoptosis and cell cycle process. The glycolysis level was examined using specific commercial kits. Western blot assay was carried out to measure the protein levels of hexokinase 2 (HK-2) and KLF12. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were employed to verify the combination between miR-876-3p and circ-RNF111 or KLF12. Murine xenograft model was constructed for the role of circ-RNF111 in vivo. Immunohistochemistry (IHC) was used for KLF12 level. RESULTS: Circ-RNF111 was higher expressed in GC tissues and cells than normal tissues and cells. Silencing of circ-RNF111 restrained cell viability, colony formation, migration, invasion, cell cycle process and glycolysis and induced apoptosis in GC cells in vitro. Circ-RNF111 positively regulated KLF12 expression via absorbing miR-876-3p. MiR-876-3p downregulation reversed the impacts of circ-RNF111 silencing on GC cell malignant phenotypes. MiR-876-3p overexpression repressed GC cell growth, metastasis and glycolysis, inhibited apoptosis and arrested cell cycle, while KLF12 elevation weakened the effects. Besides, circ-RNF111 knockdown inhibited tumor growth in vivo. CONCLUSION: Circ-RNF111 knockdown relieved the development of GC by regulating miR-876-3p/KLF12 axis.


Assuntos
Fatores de Transcrição Kruppel-Like , MicroRNAs , RNA Circular , Neoplasias Gástricas , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Humanos , Fatores de Transcrição Kruppel-Like/genética , Camundongos , MicroRNAs/genética , Proteínas Nucleares , Prognóstico , RNA Circular/genética , RNA Circular/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Ubiquitina-Proteína Ligases
19.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445212

RESUMO

Circular RNAs (circRNAs) are a new class of endogenous non-coding RNAs with covalent closed loop structure. Researchers have revealed that circRNAs play an important role in human diseases. As experimental identification of interactions between circRNA and disease is time-consuming and expensive, effective computational methods are an urgent need for predicting potential circRNA-disease associations. In this study, we proposed a novel computational method named GATNNCDA, which combines Graph Attention Network (GAT) and multi-layer neural network (NN) to infer disease-related circRNAs. Specially, GATNNCDA first integrates disease semantic similarity, circRNA functional similarity and the respective Gaussian Interaction Profile (GIP) kernel similarities. The integrated similarities are used as initial node features, and then GAT is applied for further feature extraction in the heterogeneous circRNA-disease graph. Finally, the NN-based classifier is introduced for prediction. The results of fivefold cross validation demonstrated that GATNNCDA achieved an average AUC of 0.9613 and AUPR of 0.9433 on the CircR2Disease dataset, and outperformed other state-of-the-art methods. In addition, case studies on breast cancer and hepatocellular carcinoma showed that 20 and 18 of the top 20 candidates were respectively confirmed in the validation datasets or published literature. Therefore, GATNNCDA is an effective and reliable tool for discovering circRNA-disease associations.


Assuntos
Neoplasias da Mama , Carcinoma Hepatocelular , Biologia Computacional , Bases de Dados de Ácidos Nucleicos , Neoplasias Hepáticas , Redes Neurais de Computação , RNA Circular , RNA Neoplásico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Feminino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo
20.
Gen Physiol Biophys ; 40(4): 275-287, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34350833

RESUMO

Pneumonia is a common inflammatory lung disease. Circular RNA (circRNA) vacuolar ATPase assembly factor (circ_VMA21) has been reported to mitigate the inflammatory injury in WI-38 cells. This study was to investigate the functional mechanism of circ_VMA21. Cell model was established by lipopolysaccharide (LPS) treatment in WI-38 cells. Cell cycle and apoptosis were analyzed by flow cytometry. Cell proliferation was assessed by colony formation and MTT assays. The expression quantification of circ_VMA21, microRNA-409-3p (miR-409-3p) and Kruppel-like transcription factor 4 (KLF4) was performed by qRT-PCR method. The expression of relative protein was detected by Western blot. Inflammatory response was evaluated by ELISA. The target binding was validated by dual-luciferase reporter assay. Cellular analysis indicated that LPS repressed cell cycle and proliferation but induced apoptosis. circ_VMA21 was downregulated in pneumonia samples and LPS-treated WI-38 cells. Functionally, circ_VMA21 assuaged the LPS-induced apoptotic and inflammatory damages. In addition, circ_VMA21 directly targeted miR-409-3p and its function was dependent on the sponge effect on miR-409-3p. Also, KLF4 was a target of miR-409-3p and miR-409-3p inhibitor attenuated LPS-induced cell injury by upregulating KLF4. Moreover, KLF4 was upregulated by circ_VMA21/miR-409-3p axis. These findings suggested that circ_VMA21 relieved the LPS-induced apoptotic and inflammatory injury by the regulation of miR-409-3p/KLF4 axis.


Assuntos
Lipopolissacarídeos , MicroRNAs , Apoptose , Proliferação de Células , Humanos , MicroRNAs/genética , RNA Circular
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