Auswahl der wissenschaftlichen Literatur zum Thema „Circular RNA - messenger RNA couple“

Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors are widely used for lung epidermal growth factor receptor-positive lung adenocarcinomas, but acquired resistance is inevitable. Although non-coding RNAs, such as circular RNA and microRNA, are known to play vital roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance, comprehensive analysis is lacking. Thus, this study aimed to explore the circular RNA-microRNA-messenger RNA regulatory network involved in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. Methods: To identify differentially expressed genes between the epidermal growth factor receptor-tyrosine kinase inhibitor sensitive cell line PC9 and resistant cell line PC9/ epidermal growth factor receptor-tyrosine kinase inhibitor resistance(PC9/ER), circular RNA, microRNA and messenger RNA microarrays were performed. Candidates were then identified to construct a circular RNA-microRNA-messenger RNA network using bioinformatics. Additionally, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted to evaluate the network messenger RNA, setting up a protein-protein interaction network for hub-gene identification. Afterwards, RNA immunoprecipitation was performed to enrich microRNA, and quantitative real-time PCR was used to estimated gene expression levels. Results: In total, 603, 377, and 1863 differentially expressed circular RNA, microRNA, messenger RNAs, respectively, were identified using microarray analysis, constructing a circular RNA-microRNA-messenger RNA network containing 18 circular RNAs, 17 microRNAs and 175 messenger RNAs. Moreover, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the most enriched biological process terms and pathways were related to epidermal growth factor receptor-tyrosine kinase inhibitor resistance, including Wnt and Hippo signaling pathways. Based on the competing endogenous RNA and protein-protein interaction network, circ-0007312 was showed to interact with miR-764 and both circ-0003748 and circ-0001398 were shown to interact with miR-628; both these microRNAs targeted MAPK1. Furthermore, circ-0007312, circ-0003748, circ-0001398, and MAPK1 were up-regulated, whereas miR-764 and miR-628 were downregulated in PC9/ER cells as compared to parental PC9 cells. We also found that circ-0007312 and miR-764 were positively expressed in plasma. Conclusions: Our original study associated with mechanism of target therapy in lung cancer provided a systematic and comprehensive regulation of circular RNA, microRNA and messenger RNA in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. It was found that circ-0007312- miR-764-MAPK1, circ-0003748-miR-628-MAPK1, and circ-0001398-miR-628-MAPK1 axis may play key roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance.

This study was designed to identify novel circular RNAs and the related regulatory axis to provide research targets for the diagnosis and treatment of breast cancer. The circular RNA expression microarray “GSE101123” related to breast cancer was downloaded from the Gene Expression Omnibus database. The differentially expressed circular RNAs between tumor and normal samples were screened using Limma package. The targeted microRNAs of the differentially expressed circular RNAs and the targeted messenger RNAs of the microRNAs were predicted using miRanda and miRWalk, respectively, and a circular RNAs–microRNAs–messenger RNAs network was constructed. Then, functional enrichment analysis, protein–protein interaction network construction, and drug–gene interaction analysis were conducted for the messenger RNAs. A total of 11 differentially expressed circular RNAs were identified between the breast cancer and normal samples, of which 3 were upregulated, while 8 were downregulated. The circular RNA–microRNA–messenger RNA network contained 1 circular RNA (hsa_circ_0000376), 2 microRNAs (miR-1285-3p and miR-1286), and 353 messenger RNAs. The protein–protein interaction network contained 150 nodes and 240 interactions. The hub genes in the protein–protein interaction network were all targeted messenger RNAs of miR-1285-3p that were significantly enriched in the ubiquitin–proteasome system, apoptosis, cell cycle arrest–related pathways, and cancer-related pathways involving SMAD specific E3 ubiquitin protein ligase 1, β-transducin repeat containing E3 ubiquitin protein ligase, tumor protein P53 among others. Twenty-two drugs were predicted to target 4 messenger RNAs, including tumor protein P53. A novel circular RNA, hsa_circ_0000376, was identified in breast cancer that may act as a sponge targeting miR-1285-3p expression which through its target genes, SMURF1, BTRC, and TP53, may further regulate tumorigenesis.

Introduction. Cervical cancer (CC) remains the most common cancer in women worldwide. However, effective and specific biomarkers for the diagnosis and prognosis of cervical cancer are yet to be found. In recent years, the potential of circular RNAs (circRNAs) as new diagnostic, prognostic and therapeutic tools has received much attention. The current study involved an in-depth bioinformatics research to explore the circRNA-microRNA (miRNA)-messenger RNA (mRNA) regulatory network in order to identify important molecular processes and biological pathways supposedly associated with CC. Materials and methods. The study collected data on the expression of circRNA (GSE102686), miRNA (GSE30656) and mRNA of target genes (GSE9750), based on the Gene Expression Omnibus (GEO) database, in squamous cell carcinoma of the cervix samples and normal squamous epithelium of the cervix, dividing them into study and control groups. Protein-protein interaction (PPI), Gene Ontology (GO) analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to further understand the function of circRNAs for their target genes. Results. A total of 105 differentially expressed circular RNAs (DECs), 144 differentially expressed microRNAs (DEMs), and 539 differentially expressed target genes (DEGs) were identified for cervical cancer. Concurrently, functional enrichment analysis of GO and KEGG pathways was performed for DEGs. Subsequently, searching databases for circRNA, miRNA and mRNA target genes, as well as PPI network analysis and functional enrichment revealed 3 DECs with significantly high expression levels (hsa_circ_0000745, hsa_circ_0084927 and hsa_circ_0002762), 6 DEMs with reduced expression levels (hsa -miR-145, hsa-miR-876-3p, hsa-miR-1229, hsa-miR-182, hsa-miR-520h and hsa-miR-1252) and 9 key genes such as ANGPT2, COL11A1, MEST, KIF20A, CLN6, FNDC3B, USP18, DLGAP5 and CXCL9, suggesting a potentially significant role in cervical cancer. Conclusion.Understanding the circRNA-miRNA-mRNA regulatory network is of great importance for evaluating the oncogenesis of CC, as well as discoverying new circRNAs as the main regulatory molecules in this network. This is considered to be a new direction in the diagnosis and targeted therapy of cervical cancer.

Emerging evidence demonstrates that dysregulation of circular RNA is linked to tumorigenesis and aggressive progression. However, its role in oral squamous cell carcinoma remains largely uncharacterized. In this study, we identified a novel metastasis-associated circular RNA, circular matrix metalloproteinase 9 (hsa_circ_0001162, a circular RNA derived from matrix metalloproteinase 9), which was remarkably upregulated in oral squamous cell carcinoma and positively correlated with matrix metalloproteinase 9 expression. Patients with high circular matrix metalloproteinase 9 expression were prone to lymph node metastasis and an advanced TNM stage. Importantly, circular matrix metalloproteinase 9 was identified as an efficacious diagnostic and prognostic biomarker for oral squamous cell carcinoma patients. Functional experiments showed that depletion of circular matrix metalloproteinase 9 weakened the migratory and invasive capabilities of oral squamous cell carcinoma cells in vitro as well as inhibited lung metastasis in vivo. Regarding the mechanism, circular matrix metalloproteinase 9 could simultaneously interact with AUF1 and miR-149 to block the inhibitory effect of AUF1 and miR-149 on matrix metalloproteinase 9 3′-untranslated region, resulting in enhanced matrix metalloproteinase 9 messenger RNA stability, thereby facilitating oral squamous cell carcinoma metastasis. Collectively, our data indicate that circular matrix metalloproteinase 9 acts as a metastasis-promoting gene in oral squamous cell carcinoma through regulating the messenger RNA stability of its parental gene. Therapeutic targeting of circular matrix metalloproteinase 9 may be a promising treatment intervention for metastatic oral squamous cell carcinoma patients.

Background. Circular RNA (circRNA) is a noncoding RNA that forms a closed-loop structure, and its abnormal expression may cause disease. We aimed to find potential network for circRNA-related competitive endogenous RNA (ceRNA) in atrial fibrillation (AF). Methods. The circRNA, miRNA, and mRNA expression profiles in the heart tissue from AF patients were retrieved from the Gene Expression Omnibus database and analyzed comprehensively. Differentially expressed circRNAs (DEcircRNAs), differentially expressed miRNAs (DEmiRNAs), and differentially expressed mRNAs (DEmRNAs) were identified, followed by the establishment of DEcircRNA-DEmiRNA-DEmRNA regulatory network. Functional annotation analysis of host gene of DEcircRNAs and DEmRNAs in ceRNA regulatory network was performed. In vitro experiment and electronic validation were used to validate the expression of DEcircRNAs, DEmiRNAs, and DEmRNAs. Results. A total of 1611 DEcircRNAs, 51 DEmiRNAs, and 1250 DEmRNAs were identified in AF. The DEcircRNA-DEmiRNA-DEmRNA network contained 62 circRNAs, 14 miRNAs, and 728 mRNAs. Among which, two ceRNA regulatory pairs of hsa-circRNA-100053-hsa-miR-455-5p-TRPV1 and hsa-circRNA-005843-hsa-miR-188-5p-SPON1 were identified. In addition, six miRNA-mRNA regulatory pairs including hsa-miR-34c-5p-INMT, hsa-miR-1253-DDIT4L, hsa-miR-508-5p-SMOC2, hsa-miR-943-ACTA1, hsa-miR-338-3p-WIPI1, and hsa-miR-199a-3p-RAP1GAP2 were also obtained. MTOR was a significantly enriched signaling pathway of host gene of DEcircRNAs. In addition, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy were remarkably enriched signaling pathways of DEmRNAs in DEcircRNA-DEmiRNA-DEmRNA regulatory network. The expression validation of hsa-circRNA-402565, hsa-miR-34c-5p, hsa-miR-188-5p, SPON1, DDIT4L, SMOC2, and WIPI1 was consistent with the integrated analysis. Conclusion. We speculated that hsa-circRNA-100053-hsa-miR-455-5p-TRPV1 and hsa-circRNA-005843-hsa-miR-188-5p-SPON1 interaction pairs may be involved in AF.

RNAs of different shapes and sizes, natural or synthetic, can regulate gene expression in prokaryotes and eukaryotes. Circular RNAs have recently appeared to be more widespread than previously thought, but their role in prokaryotes remains elusive. Here, by inserting a riboregulatory sequence within a group I permuted intron-exon ribozyme, we created a small noncoding RNA that self-splices to produce a circular riboregulator in Escherichia coli. We showed that the resulting riboregulator can trans-activate gene expression by interacting with a cis-repressed messenger RNA. We characterized the system with a fluorescent reporter and with an antibiotic resistance marker, and we modeled this novel posttranscriptional mechanism. This first reported example of a circular RNA regulating gene expression in E. coli adds to an increasing repertoire of RNA synthetic biology parts, and it highlights that topological molecules can play a role in the case of prokaryotic regulation.

The current researches have reported that circular RNA is an important regulatory factor in the progression of various human disease. However, the function and mechanism of most circular RNAs remain unknown in cancers including multiple myeloma. Our study has confirmed that hsa_circ_0007841 is up regulated in U266 doxorubicin resistant cells (U266R) and 8226 doxorubicin resistant cells (8226R) compared to U266 parent cells (U266P) and 8226 parent cells (8226P). Silence of hsa_circ_0007841 in U266R and 8226R could reduce the half-maximal inhibitory concentration which indicated reduction in chemoresistance. In doxorubicin resistant cells, the messenger RNA and protein level of ATP-binding cassette transporters G2 increased. Silence of hsa_circ_0007841 in drug resistant cells could decrease both the messenger RNA and protein levels of ATP-binding cassette transporters G2; reexpression of hsa_circ_0007841 could block the reduction. However, overexpression of hsa_circ_0007841 could effectively upregulate the ATP-binding cassette transporters G2 messenger RNA and protein level. Inhibition of ATP-binding cassette transporters G2 could block hsa_circ_0007841 overexpression induced chemoresistance in U266P and 8226P cells. What’s more, inhibition of ATP-binding cassette transporters G2 could reduce differences of half-maximal inhibitory concentration between parent cell lines and drug-resistant cell lines. Our data collectively suggest a new model in which hsa_circ_0007841 promotes acquired chemotherapy resistance by upregulating ATP-binding cassette transporters G2 providing a novel molecular basis of chemotherapy in multiple myeloma cancer.

RNA vaccines, including conventional messenger RNA (mRNA) vaccines, circular RNA (circRNA) vaccines, and self-amplifying RNA (saRNA) vaccines, have ushered in a promising future and revolutionized vaccine development. The success of mRNA vaccines in combating the COVID-19 pandemic caused by the SARS-CoV-2 virus that emerged in 2019 has highlighted the potential of RNA vaccines. These vaccines possess several advantages, such as high efficacy, adaptability, simplicity in antigen design, and the ability to induce both humoral and cellular immunity. They also offer rapid and cost-effective manufacturing, flexibility to target emerging or mutant pathogens and a potential approach for clearing immunotolerant microbes by targeting bacterial or parasitic survival mechanisms. The self-adjuvant effect of mRNA-lipid nanoparticle (LNP) formulations or circular RNA further enhances the potential of RNA vaccines. However, some challenges need to be addressed. These include the technology’s immaturity, high research expenses, limited duration of antibody response, mRNA instability, low efficiency of circRNA cyclization, and the production of double-stranded RNA as a side product. These factors hinder the widespread adoption and utilization of RNA vaccines, particularly in developing countries. This review provides a comprehensive overview of mRNA, circRNA, and saRNA vaccines for infectious diseases while also discussing their development, current applications, and challenges.

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.

Les ARN circulaires (ARNcirc), produits du rétro-épissage, sont une nouvelle classe émergente d’ARN impliquée dans diverses maladies et notamment le cancer. Ces ARNcirc, par leurs multiples fonctions, peuvent moduler les niveaux des ARN messagers (ARNm), transcrits linéaires finement régulés. Etant donné que physiologiquement un équilibre s’opère entre ces deux types de transcrits, nous faisons l’hypothèse qu’une perturbation des niveaux de ce couple ARNcirc-ARNm joue un rôle dans la tumorigenèse. Pour tester cette hypothèse, nous avons développé SEALigHTS (Splice and Expression Analyses by exon Ligation and High Throughput Sequencing), une technique innovante permettant l’analyse simultanée des ARNcirc et des ARNm. SEALigHTS se base sur la modélisation de sondes aux extrémités des exons, autorisant l’exploration de toutes les jonctions exon-exon. Brièvement, après une rétrotranscription et l’hybridation des sondes à l’ADN complémentaire, les sondes avoisinantes sont liguées. Le nombre de ligations est ensuite quantifié, par l’utilisation d’UMI (Unique Molecular Identifiers) séquencés. Dans un premier temps, nous avons analysé des échantillons de tissus mammaires tumoraux et normaux adjacents. L’analyse de l’épissage et du rétro-épissage des gènes BRCA1 et BRCA2, impliqués dans le syndrome sein et ovaire, a révélé une diminution significative du ratio ARNcirc/ARNm dans le tissu tumoral en comparaison au tissu normal (p = 1,6e-09 pour BRCA1 et p = 4,4e-05 pour BRCA2). Dans un deuxième temps, nous avons étudié l'épissage et le rétro-épissage de 23 gènes de prédisposition au cancer colorectal (CCR) sur des échantillons sanguins de 712 patients prédisposés au CCR et de 249 témoins. Le ratio ARNcirc/ARNm s'est avéré 1,93 fois plus élevé chez les patients que chez les témoins (p < 2e-16). Dans un troisième temps, nous avons évalué le potentiel diagnostique de SEALigHTS par l’étude de 44 gènes de prédisposition au CCR et au syndrome sein et ovaire. Après validation de la détection des événements d’épissage de variations caractérisées, l’analyse de patients prospectifs a permis d’améliorer le rendement diagnostique. Cette étude a enrichi nos connaissances sur les niveaux des différentes isoformes linéaires et circulaires des gènes étudiés. Au-delà de leur potentiel en tant que biomarqueurs dans le cancer du sein ou le CCR, la perturbation du ratio ARNcirc/ARNm soulève des questions sur l'implication des ARNcirc en génétique somatique et constitutionnelle
Circular RNAs (circRNAs), produced by backsplicing, are an emerging new class of RNAs implicated in various diseases, including cancer. Through their multiple functions, circRNAs can modulate the levels of messenger RNAs (mRNAs), finely regulated linear transcripts. Given that a physiologically balance exists between these two types of transcripts, we hypothesize that a disruption in the levels of this circRNA-mRNA couple plays a role in tumorigenesis. To test this hypothesis, we developed SEALigHTS (Splice and Expression Analyses by exon Ligation and High Throughput Sequencing), an innovative technique for the simultaneous analysis of circRNAs and mRNAs. SEALigHTS is based on the design of probes at exon ends, enabling exploration of all exon-exon junctions. Briefly, after reverse transcription and hybridization of probes to complementary DNA, neighboring probes are ligated, and the number of ligations quantified using unique molecular identifiers and sequencing. As a first step, we analyzed tumor and adjacent normal breast tissue samples. Analysis of the splicing and backsplicing of BRCA1 and BRCA2 genes, involved in Hereditary Breast and Ovarian Cancer syndrome (HBOC), revealed a significant decrease in the circRNA/mRNA ratio in tumor tissue compared to normal tissue (p = 1.6e-09 for BRCA1 and p = 4.4e-05 for BRCA2). In a second step, we studied the splicing and backsplicing of 23 colorectal cancer (CRC) predisposition genes in blood samples from 712 CRC-predisposed patients and 249 controls. The circRNA/mRNA ratio was found to be 1.93 times higher in patients than in controls (p < 2e-16). In a third step, we assessed the diagnostic potential of SEALigHTS by studying 44 CRC and HBOC genes. After validating the detection of splicing events for characterized variations, the analysis of prospective patients with SEALigHTS improved the diagnostic yield. This study has enriched our knowledge of the levels of the various linear and circular isoforms of the predisposition genes studied. Beyond their potential as biomarkers in breast cancer or CRC, the disruption of the circRNA/mRNA ratio raises questions about the involvement of circRNAs in somatic and constitutional genetics

Abstract Plant viruses are distinct from other major host-related groupings of viruses, such as animal or bacterial viruses, in that they are mostly single-stranded messenger-sense ss(+)RNA viruses, and mostly have simple, non-enveloped virions. There are a large number of types of simple isometric viruses, such as the Bromoviridae, Tombusviridae, and Comoviridae, as well as a wide variety of flexuous filamentous or rodlike types with helical capsid symmetry, such as the Potyviridae, Closteroviridae, and Tobamoviruses (1). There are some exceptions, notably with virus families that span different groups. Thus there are the enveloped ss(-)RNA plant Rhabdoviridae and Bunyaviridae, and the naked isometric dsRNA-containing plant Reoviridae (all of which may replicate in insect vectors and in insect cell cultures); there are two distinct groups of naked isometric ssDNA viruses with circular genomes (Geminiviridae and Nanoviruses) and two distinct groupings of plant pararetroviruses (Caulimo viridae and Badnaviruses) (2). While plant viruses as a group may not be as generally labile as their animal counterparts, given fewer enveloped viruses, it may be seen that there is considerable diversity, meaning that culture methods and methods for purification are similarly diverse.

Abstract In many research fields that impact directly on clinical medicine (e.g. wound healing) a new emphasis on the examination of human tissue has emerged facilitated by the availability of more sophisticated laboratory techniques. This immediately defines the limiting factor in choosing an assay as the volume of human tissue available. To investigate human growth factor and re ceptor gene expression in any depth, assessment of both protein and messenger RNA (mRNA) for ligand and receptor must be made, in terms both of quantity and of distribution, on small tissue samples. 6 mm punch biopsy wounds of skin for example can be sutured directly, or converted into a small ellipse. In the former case the sutures tend to pull out to leave a pale, circular scar, and in the latter a linear scar of&lt; 1 cm length remains. A 6 mm punch biopsy of skin provides around 60 mg wet weight of tissue. For protocols that require repeated biopsy of an individual, 3 mm punch biopsies are preferable. These can be left to heal by secondary intention, leaving a minimal ‘pit’ scar. Note: researchers must meet all local and/or national ethical requirements before taking biopsies for experimental purposes from human subjects.