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A novel miRNA-4484 is up-regulated on microarray and associated with increased MMP-21 expression in serum of systemic sclerosis patients

ABSTRACT: Systemic sclerosis (SSc) is a complex, heterogeneous connective tissue disease, characterized by fibrosis and ECM deposition in skin and internal organs, autoimmunity, and changes in the microvasculature. Profiling of circulating miRNAs in serum has been found to be changed in pathological states, creating new possibilities for molecular diagnostics as blood-based biomarkers. This study was designed to identify miRNAs that are differentially expressed in SSc and might be potentially contributing to the disease etiopathogenesis or be used for diagnostic purposes. Thus, we compared the expression pattern of multiple miRNAs in serum of 10 SSc patients to 6 healthy controls using microarray analysis, and RT-qPCR to confirm the obtained results. In addition, bioinformatics analysis was performed to explore miRNAs target genes and the signaling pathways that may be potentially involved in SSc pathogenesis. Our study shows a different expression of 15 miRNAs in SSc patients. We identified that miR-4484, located on chromosome 10q26.2, was an 18-fold up-regulated in SSc patients compared to a control group. Bioinformatics analysis of the miR-4484 target genes and the signaling pathways showed that it might be potentially involved in the TGF-β signaling pathway, ECM-receptor interaction, and metalloproteinases expression. Based on the chromosomal location, the most interesting target gene of miR-4484 may be MMP-21. We found that the expression of MMP-21 significantly increased in SSc patients compared to healthy subjects (P<0.05). Our results suggest that miR-4484, and MMP-21 might be novel serum biomarkers that may correspond to pathological fibrosis in SSc, but it needs to be validated in further studies.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE137472 | GEO | 2019/10/15

REPOSITORIES: GEO

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Project description:To investigate the miRNA signature in the serum of systemic sclerosis (SSc) patients. The levels of 758 miRNAs were evaluated in the serum of 26 SSc patients as compared to 9 healthy controls by using an Openarray platform. Patients fulfilling the ACR/EULAR 2013 classification criteria were classified in relation to the extent of skin fibrosis as limited cutaneous (lcSSc) or diffuse cutaneous SSc (dcSSc); patients fulfilling the classification criteria without skin fibrosis will be referred to as non-cutaneous SSc (ncSSc). MicroRNAs (miRNAs) are regulatory molecules, which have been addressed as potential biomarkers and therapeutic targets in rheumatic diseases. Here, we investigated the miRNA signature in the serum of systemic sclerosis (SSc) patients and we further assessed their expression in early stages of the disease.The levels of 758 miRNAs were evaluated in the serum of 26 SSc patients as compared to 9 healthy controls by using an Openarray platform. Three miRNAs were examined in an additional cohort of 107 SSc patients and 24 healthy donors by single qPCR. MiR-483-5p expression was further analysed in the serum of patients with localized scleroderma (LoS) (n=22), systemic lupus erythematosus (SLE) (n=33) and primary Sjögren’s syndrome (pSS) (n=23). The function of miR-483-5p was examined by transfecting miR-483-5p into primary human dermal fibroblasts and pulmonary endothelial cells.30 miRNAs were significantly increased in patients with SSc. Of these, miR-483-5p showed reproducibly higher levels in an independent SSc cohort and was also elevated in patients with preclinical-SSc symptoms (early SSc). Notably, miR-483-5p was not differentially expressed in patients with SLE or pSS, whereas it was up-regulated in LoS, indicating that this miRNA could be involved in the development of skin fibrosis. Consistently, miR-483-5p overexpression in fibroblasts and endothelial cells modulated the expression of fibrosis-related genes.Our findings showed that miR-483-5p is up-regulated in the serum of SSc patients, from the early stages of the disease onwards, and indicated its potential function as a fine regulator of fibrosis in SSc.

Project description:Oxidative stress is involved in the human diseases and developmental retardation of animals. The molecular mechanisms that mediate the response of neuron to oxidative stress have been extensively studied. MicroRNAs (MiRNAs) are a type of small non-coding RNAs that regulate nearly all aspects of nerve development and survival, including apoptosis. However, the effect of oxidative stress on the expression of miRNAs of hippocampus of Rongchang piglets, which are regarded as the good production animal and biomedical model has not been investigated. In this study, oxidative stress was induced in newborn piglets by means of intra-muscular injection of iron. Injection of iron significantly increased several markers of oxidative stress in serum of Rongchang piglets. RNA-sequencing (RNA-seq) technology and bioinformatics were used to uncover the differently expressed miRNAs and target genes induced by oxidative stress in the ventral hippocampus (VH) and dorsal hippocampus (DH) of Rongchang piglets, respectively. Results revealed 2790 conserved miRNAs belonging to 279 miRNA families, 326 known miRNAs and 702 novel miRNAs. The sub-tissue specificity was displayed with 54 differentially expressed miRNAs being found between VH and DH. At the same time, the injection of iron induced 59 and 46 differentially expressed miRNAs in VH and DH, respectively. The analysis of target genes showed that 6 known miRNAs (ssc-miR-183, ssc-miR-383, ssc-miR-193a-5p, ssc-miR-182, ssc-miR-7138-5p and ssc-miR-1271) commonly targeted to ADM2. In addition, GO and KEGG pathway analysis showed that these differentially expressed miRNAs induced by the injection of iron were involved in the pathways that regulate the expression of genes associated with oxidative stress. Our study provided an overview of miRNAs expression profile of functional sub-region of hippocampus in Rongchang piglets and shed light into the significantly changed miRNAs after the injection of iron, which will lead to further understanding of the important roles of miRNAs in hippocampus of Rongchang piglets during the process of oxidative stress.

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A novel miRNA-4484 is up-regulated on microarray and associated with increased MMP-21 expression in serum of systemic sclerosis patients

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