Dataset Information

Down-regulated miR-495 can target programmed cell death 10 in ankylosing spondylitis.

ABSTRACT:

Background

MicroRNAs (miRNAs) play crucial roles in regulating eukaryotic gene expression. Recent studies indicated that aberrantly expressed miRNAs are involved in the pathogenesis of ankylosing spondylitis (AS). Indeed, hsa-miR-495-3p (miR-495) has been reported as an anti-oncogene in different cancers. However, the role of miR-495 in AS is still unknown.

Methods

In this study, quantitative real-time polymerase chain reaction (PCR) was used to detect the expression of miR-495 in the peripheral blood mononuclear cells (PBMCs), whole blood, and serum of patients with AS. Bisulfite-specific PCR sequencing and methylated DNA immunoprecipitation were used to detect the methylation in the promoter region of miR-495. To determine the influence of miR-495 expression on the target gene, programmed cell death 10 (PDCD10), dual luciferase reporter assays together with an adenoviral vector containing the miR-495 locus were used. Receiver operating characteristic (ROC) curves were used to evaluate the efficacy of miR-495 as a diagnostic biomarker of AS. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway analysis, and western blotting were used to explore the potential role of miR-495 in AS pathogenesis and the mechanism by which it facilitates AS pathogenesis.

Results

miR-495 is down-regulated and the promoter region of miR-495 is highly methylated in AS. The expression of miR-495 is negatively associated with PDCD10 expression in both patients with AS and healthy controls. Further experiments showed that PDCD10 can be targeted by miR-495. The ROC curves of miR-495 suggested that it is a very specific and sensitive biomarker for AS diagnosis. Bioinformatics analysis and signal pathway studies indicated that miR-495 can down-regulate ?-catenin and transforming growth factor-?1.

Conclusions

Our studies indicated that down-regulation of miR-495 can be used as a potential molecular marker for the diagnosis and treatment of AS, thus providing new insights into the role of miRNAs in AS pathology.

SUBMITTER: Ni WJ

PROVIDER: S-EPMC7249445 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

Down-regulated miR-495 can target programmed cell death 10 in ankylosing spondylitis.

Ni Wen-Juan WJ Leng Xiao-Min XM

Molecular medicine (Cambridge, Mass.) 20200525 1

<h4>Background</h4>MicroRNAs (miRNAs) play crucial roles in regulating eukaryotic gene expression. Recent studies indicated that aberrantly expressed miRNAs are involved in the pathogenesis of ankylosing spondylitis (AS). Indeed, hsa-miR-495-3p (miR-495) has been reported as an anti-oncogene in different cancers. However, the role of miR-495 in AS is still unknown.<h4>Methods</h4>In this study, quantitative real-time polymerase chain reaction (PCR) was used to detect the expression of miR-495 in ...[more]

PMID: 32450789

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Project description:Ankylosing spondylitis (AS) stands as a persistent inflammatory ailment predominantly impacting the axial skeleton, with the immune system and inflammation intricately entwined in its pathogenesis. This study endeavors to elucidate gender-specific patterns in immune cell infiltration and diverse forms of cell demise within the AS milieu. The aim is to refine the diagnosis and treatment of gender-specific AS patients, thereby advancing patient outcomes. In the pursuit of our investigation, two datasets (GSE25101 and GSE73754) pertinent to ankylosing spondylitis (AS) were meticulously collected and normalized from the GEO database. Employing the CIBERSORT algorithm, we conducted a comprehensive analysis of immune cell infiltration across distinct demographic groups and genders. Subsequently, we discerned differentially expressed genes (DEGs) associated with various cell death modalities in AS patients and their healthy counterparts. Our focus extended specifically to ferroptosis-related DEGs (FRDEGs), cuproptosis-related DEGs (CRDEGs), anoikis-related DEGs (ARDEGs), autophagy-related DEGs (AURDEGs), and pyroptosis-related DEGs (PRDEGs). Further scrutiny involved discerning disparities in these DEGs between AS patients and healthy controls, as well as disparities between male and female patients. Leveraging machine learning (ML) methodologies, we formulated disease prediction models employing cell death-related DEGs (CDRDEGs) and identified biomarkers intertwined with cell death in AS. Relative to healthy controls, a myriad of differentially expressed genes (DEGs) linked to cell death surfaced in AS patients. Among AS patients, 82 FRDEGs, 29 CRDEGs, 54 AURDEGs, 21 ARDEGs, and 74 PRDEGs were identified. In male AS patients, these numbers were 78, 33, 55, 24, and 94, respectively. Female AS patients exhibited 66, 41, 40, 17, and 82 DEGs in the corresponding categories. Additionally, 36 FRDEGs, 14 CRDEGs, 19 AURDEGs, 10 ARDEGs, and 36 PRDEGs exhibited differential expression between male and female AS patients. Employing machine learning techniques, LASSO, RF, and SVM-RFE were employed to discern key DEGs related to cell death (CDRDDEGs). The six pivotal CDRDDEGs in AS patients, healthy controls, were identified as CLIC4, BIRC2, MATK, PKN2, SLC25A5, and EDEM1. For male AS patients, the three crucial CDRDDEGs were EDEM1, MAP3K11, and TRIM21, whereas for female AS patients, COX7B, PEX2, and RHEB took precedence. Furthermore, the trio of DDX3X, CAPNS1, and TMSB4Y emerged as the key CDRDDEGs distinguishing between male and female AS patients. In the realm of immune correlation, the immune infiltration abundance in female patients mirrored that of healthy controls. Notably, key genes exhibited a positive correlation with T-cell CD4 memory activation when comparing male and female patient samples. This study engenders a more profound comprehension of the molecular underpinnings governing immune cell infiltration and cell death in ankylosing spondylitis (AS). Furthermore, the discernment of gender-specific disparities among AS patients underscores the clinical significance of these findings. By identifying DEGs associated with diverse cell death modalities, this study proffers invaluable insights into potential clinical targets for AS patients, taking cognizance of gender-specific nuances. The identification of gender-specific biological targets lays the groundwork for the development of tailored diagnostic and therapeutic strategies, heralding a pivotal step toward personalized care for AS patients.

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Project description:We have compared synovial biopsies from ankylosing spondylitis and undifferentiated spondylitis patients with healthy controls and osteoarthritis patients Objective: In spondylarthropies, whole-genome gene expression profiling studies have been limited to peripheral blood to date. By undertaking a study in knee synovial biopsies from spondylarthropy (SpA) and ankylosing spondylitis (AS) patients we aimed to identified joint-specific candidate genes and pathways. These pathways may mediate systemic inflammation driven joint damaging processes and more specifically, the osteoproliferation that is characteristic of these conditions. Methods: RNA was extracted from six seronegative SpA, two AS, three osteoarthritis (OA) and four normal control knee synovial biopsies. Whole genome expression profiling was undertaken using the Illumina DASL system, which assays 24000 cDNA probes. Differentially expressed candidate genes were then validated using quantitative PCR and immunohistochemistry. Results: 416 differentially expressed genes were identified that clearly delineated between AS/SpA and control groups. Pathway analysis showed altered gene-expression in oxidoreductase activity, osteoblast activity, B-cell associated, matrix catabolic, and metabolic pathways. The inflammatory mediator, MMP3, was strongly upregulated in AS/SpA samples and the Wnt pathway inhibitors DKK3 and Kremen1 were downregulated. Conclusion: Pathways mediating both systemic inflammation as well as local tissue changes were identified. This suggests initial systemic inflammation in spondylarthropies transfers to and persists in the local joint environment, subsequently mediating changes in genes directly involved in the destructive tissue remodelling. Fifteen knee synovial biopsy tissue samples consisting of six seronegative spondyloarthropy (SpA), two ankylosing spondylitis (AS), three osteoarthritis (OA) and four normal control biopsies were obtained from the Synovial Tissue Bank at the Repatriation General Hospital in Adelaide, South Australia with the appropriate ethical approval (Supplementary Table 1). All patients provided informed written consent.

Dataset Information

Down-regulated miR-495 can target programmed cell death 10 in ankylosing spondylitis.

Background

Methods

Results

Conclusions

Publications

Down-regulated miR-495 can target programmed cell death 10 in ankylosing spondylitis.

Similar Datasets

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