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Serum microRNA screening and functional studies reveal miR-483-5p as a potential driver of fibrosis in systemic sclerosis

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE108918 | GEO | 2018/02/15

REPOSITORIES: GEO

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Project description:MicroRNAs (miRNAs) are abundant in the circulation and play a central role in diverse biological processes; they may be useful for early diagnosis of hepatocellular carcinoma (HCC). We conducted a two-phase, case-control study (20 pairs for the discovery set and 49 pairs for the validation set) to test the hypothesis that genome-wide dysregulation of circulating miRNAs differentiate HCC cases from controls. Taqman low density arrays were used to examine genome-wide miRNA expression for the discovery set, and quantitative RT-PCR was used to validate candidate miRNAs for both discovery and validation sets. Sixty-six miRNAs were found to be significantly over-expressed in plasma of HCC cases compared to controls after adjusting for false discovery rate (p<0.05). A volcano plot indicated that 7 miRNAs had greater than 2-fold case-control differences with p<0.01. Four significant miRNAs (miR-150, miR-30c, miR-483-5p and miR-520b) detectable in all samples with varied expression levels were further validated in a validation set. MiR-483-5p was statistically significantly over-expressed in HCC cases compared with controls (3.20 vs. 0.82, p<0.0001). HCC risk factors and clinic-pathological characteristics did not influence miR-483-5p expression. The combination of plasma miR-483-5p level and HCV status can significantly differentiate HCC cases from controls with an AUC of 0.908 (p<0.0001). The sensitivity and specificity were, respectively, 75.5% and 89.8%. These preliminary results suggest the importance of dysregulated circulating miR-483-5p as a potential HCC biomarker. Confirmation of aberrant expression of miR-483-5p in a large prospective HCC study will provide support for its application to HCC detection. A hospital-based HCC case-control study including 20 HCC patients and 20 controls is conducted in Columbia University Medical Center (CUMC), which is approved by the Institutional Review Board. Cases were newly diagnosed HCC patients who were treated in the Hepatobiliary Oncology Clinics, CUMC, and examined pathologically. Controls were recruited from volunteers through the Research Recruitment and Minority Outreach (RRMO) core of Herbert Irving Comprehensive Cancer Center (HICCC). Flyers were placed at strategic locations around CUMC where hospital visitors and employees frequent or were handed out at inreach events at the hospital or at outreach events in the community. Interested participants were directed to contact the trained recruitment staff from the RRMO and given further information about participation. Interested participants were excluded from the control group if diagnosed for any kind of cancer or liver disease. Eligible controls were asked to fill out the same demographic and epidemiological questionnaire as HCC cases. In the current study, controls were matched with HCC cases on age (M-BM-15 yrs), gender (male/female) and ethnicities (Caucasian/Hispanic/African-American/Asian).

Project description:Background/Aim: We investigated alterations in the expression of serum exosomal miRNAs with the progression of liver fibrosis and evaluated their clinical applicability as biomarkers. Methods: This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. Methods: This study prospectively enrolled 71 patients who underwent liver biopsy at an academic hospital in Korea. Exosomes were extracted from serum samples, followed by next-generation sequencing (NGS) of miRNAs and targeted real-time quantitative polymerase chain reaction. A model was derived to discriminate advanced fibrosis based on miRNA levels and the performance of this model was evaluated. Validation of the effect of miRNA on liver fibrosis in vitro was followed. Results: NGS data revealed that exosomal miR-660-5p, miR-125a-5p, and miR-122 expression were changed significantly with the progression of liver fibrosis, of which miR-122 exhibited high read counts enough to be used as a biomarker. The level of exosomal miR-122 decreased as the pathologic fibrosis grade progressed and patients with biopsy-proven advanced fibrosis had significantly lower levels of exosomal miR-122 (P < 0.001) than those without advanced fibrosis. Exosomal miR-122 exhibited a fair performance in discriminating advanced fibrosis especially in combination with fibrosis-4 score and transient elastography. In a subgroup of patients with a non-viral etiology of liver disease, the performance of exosomal miR-122 as a biomarker was greatly improved. Inhibition of miR-122 expression increased the proliferation of the human hepatic stellate cell line, LX-2, and upregulated the expression of various fibrosis related proteins. Conclusion: Exosomal miR-122 may serve as a useful non-invasive biomarker for liver fibrosis, especially in patients with non-viral etiologies of chronic liver disease.

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Serum microRNA screening and functional studies reveal miR-483-5p as a potential driver of fibrosis in systemic sclerosis

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