MiR-146a-5p contributes to inflammation-mediated β cell mitochondrial dysfunction and apoptosis
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ABSTRACT:
PROVIDER: PRJNA1076462 | ENA |
REPOSITORIES: ENA
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Project description:MicroRNAs (miRNAs) are small non-coding RNAs that function as modulators of gene expression. We previously showed that miR-146a-5p is upregulated in pancreatic islets treated with pro-inflammatory cytokines and in pancreatic sections from organ donors with type 1 diabetes (T1D). Other studies have associated overexpression of miR-146a-5p with β cell apoptosis and impaired insulin secretion; however, the molecular mechanisms mediating these effects remain elusive. To investigate the role of miR-146a-5p in β cell function, we developed stable MIN6 cell lines transduced with lentiviral vectors to either overexpress or inhibit the expression of miR-146a-5p. Monoclonal cell populations were treated with pro-inflammatory cytokines (IL1β, IFNg, and TNFα) to model T1D in vitro. We found that overexpression of miR-146a-5p increased the cell death of MIN6 cells under inflammatory stress, whereas inhibition of miR-146a-5p reversed these effects. Additionally, inhibition of miR-146a-5p increased mitochondrial DNA copy number, respiration rate, and ATP production, suggesting that miR-146a-5p inhibition improves mitochondrial function. In support of this finding, we also observed that miR-146a-5p is enriched in the mitochondria of MIN6 cells treated with cytokines. Consistently, bioinformatic analysis of RNA sequencing data using MIN6 stable cells showed enrichment of pathways related to insulin secretion, apoptosis, and mitochondrial function when the expression levels of miR-146a-5p were altered. Overall, the findings from our study show for the first time that miR-146a-5p upregulation during inflammatory stress may promote β cell dysfunction and death by suppressing mitochondrial function.
2024-04-10 | GSE255756 | GEO
Project description:MiR-146a downregulation contributes to sunitinib-induced cardiac dysfunction
| PRJNA518091 | ENA
Project description:Analysis of human mesenchymal stem cells (MSC) from bone marrow and the Wharton's jelly of the umbilical cord after manupulating miR-146a-5p expression. miR-146a-5p is involved in controlling the proliferation and migration of MSCs. Results provide miR-146a-5p-regulating genes in MSCs. In this study, BM-MSCs transduced with miR-146a-5p expression vector or pCDH-CMV-MCS-EF1-copGFP vector only, as well as two WJ-MSCs transfected with short interfering RNAs targeting miR-146a or a GFP control.
2013-09-05 | E-GEOD-44186 | biostudies-arrayexpress
Project description:Analysis of human mesenchymal stem cells (MSC) from bone marrow and the Wharton's jelly of the umbilical cord after manupulating miR-146a-5p expression. miR-146a-5p is involved in controlling the proliferation and migration of MSCs. Results provide miR-146a-5p-regulating genes in MSCs.
2013-09-05 | GSE44186 | GEO
Project description:We established stable miR-146a-5p overexpression T24 cells, then performed transcriptome profiling of miR-146a-5p overexpressing cells compared to control T24 cells to detect the molecular mechanisms of the miR-146a-5p’s effect on bladder cancer cells.
2024-02-03 | GSE166139 | GEO
Project description:Hepatitis C virus (HCV)-induced chronic liver disease is one of the leading causes of hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying HCC development following chronic HCV infection remain poorly understood. MicroRNAs (miRNAs) play an important role in cellular homeostasis within the liver and deregulation of the miRNome has been associated with liver disease including HCC. While host miRNAs are essential for HCV replication, viral infection in turn appears to induce alterations of intrahepatic miRNA networks. Although the cross-talk between HCV and liver cell miRNAs most likely contributes to liver disease pathogenesis, the functional involvement of miRNAs in HCV-driven hepatocyte injury and HCC remains elusive. Here, we combined a hepatocyte-like based model system, high-throughput small RNA-sequencing, computational analysis and functional studies to investigate HCV-miRNA interactions that may contribute to liver disease and HCC. Profiling analyses indicated that HCV infection differentially regulated the expression of 72 miRNAs by at least two-fold including miRNAs that were previously described to target genes associated with inflammation, fibrosis and cancer development. Further investigation demonstrated that miR-146a-5p was consistently increased in HCV-infected hepatocyte-like cells and primary human hepatocytes as well as in liver tissues from HCV-infected patients. Genome-wide microarray and computational analyses indicated that miR-146a-5p over-expression is related to liver disease and HCC development. Furthermore, we showed that miR-146a-5p positively impacts on late steps of the viral replication cycle thereby increasing HCV infection. Collectively, our data indicate that the HCV-induced increase in miR-146a-5p expression both promotes viral infection and is relevant for pathogenesis of liver disease. To explore the functional relevance of miR-146a-5p up-regulation, we performed a genome-wide transcriptomic analysis of hepatocyte-like cells upon ectopic miR-146a-5p expression.
2016-05-09 | GSE79340 | GEO
Project description:Ovarian cancer is a malignant gynecologic disease rarely diagnosed in the early stages. Among ovarian cancers, clear cell carcinoma has a poor prognosis due to its malignant potential. MicroRNAs (miRNAs) regulate gene expression in cells by suppressing the translation of the target gene or by degrading the target mRNA. They are also secreted from the cells in the blood, binding to the proteins or lipids and assisting in cell-cell communication. Hence, serum miRNAs can also be diagnostic biomarkers for ovarian cancer. This study investigated and identified specific miRNAs for ovarian clear cell carcinoma and compared them to those of ovarian endometrioma in healthy patients. CA125, an ovarian tumor marker, did not differ between patients with ovarian clear cell carcinoma, endometriosis, or healthy controls. Four miRNAs (miR-146a-5p, miR-191-5p, miR-484, and miR-574-3p) were analyzed. The miR-146a-5p and miR-191-5p expression levels were significantly increased in the serum samples from the patients with ovarian clear cell carcinoma compared to the healthy controls but not in the patients with endometriosis (P < 0.05). Furthermore, the bioinformatics analysis showed that CCND2 and NOTCH2 were the candidate target genes of miR 146a-5p and miR-191-5p. In conclusion, our results showed that miR 146a-5p and miR-191-5p might be useful as early and non-invasive diagnostic tools in ovarian clear cell carcinoma. These miRNAs can help in distinguishing between ovarian clear cell carcinoma and ovarian endometrioma. To the best of our knowledge, no studies have screened any candidates specifically for clear cell carcinoma.
2023-10-06 | GSE239685 | GEO
Project description:Bladder cancer characterized by RNA methylation abnormalities and NOTCH pathway dysregulation exhibits high recurrence that remains the major obstacle for bladder cancer treatment. Targeting methyltransferase-like 3 (METTL3) and NOTCH signal is a potential strategy to block bladder cancer progression. However, the underlying mechanisms by which METTL3-manipulated NOTCH signal and its effect on bladder cancer tumorigenesis remain to be clarified. Here we showed that METTL3-guided m6A modification methylated pri-miR-146 at the flaking sequence, which was responsible for the pri-miR-146 maturation. Furthermore, NUMB/NOTCH2 axis was identified as the functional downstream target signal that mediated the pro-survival role of miR-146a-5p in bladder cancer cells. Therapeutically, the polypeptide melittin was demonstrated to induce apoptosis of bladder cancer cells in a METTL3-dependent manner. Importantly, METTL3 and miR-146a-5p were positively correlated with recurrence and poor prognosis of bladder cancer patient. Our studies indicate that METTL3/miR-146a-5p/NUMB/NOTCH2 axis could be a potential therapeutic target for recurrent bladder cancer treatment and METTL3 acts as a fate determinant that controls sensitivity of bladder cancer cells to melittin treatment.
2024-10-01 | GSE185272 | GEO
Project description:In our previous study, hsa-let-7d-3p, hsa-let-7e-5p,hsa-miR-146a-5p,hsa-miR-130a-3p, hsa-miR-151a-3p,were significantly upregulated in the plasma of atopic patients. To study the each function of let-7d-3p, let-7e-5p,miR-146a-5p,miR-130a-3p, miR-151a-3p which are significantly upregulated in the plasma of atopic patients, we performed mimic-transfected THP-1 cells, a mononuclear cell line, and performed comprehensive genetic analysis.
2023-02-06 | GSE217971 | GEO
Project description:Inflammatory b-cell failure contributes to type 1 and type 2 diabetes pathogenesis. Proinflammatory cytokines cause b-cell dysfunction and apoptosis, and lysine deacetylase inhibitors (KDACi) prevent b-cell failure in vitro and in vivo, in part by reducing NFkB transcriptional activity. Here we investigated the hypothesis that the protective effect of KDACi involves transcriptional regulation of microRNAs (miRs), potential new targets in diabetes treatment. Insulin-producing INS1 cells were cultured with or without the broad-spectrum KDACi Givinostat prior to exposure to the proinflammatory cytokines IL-1-b and IFN-g for 6h or 24h, and miR expression was profiled with miR array. A shortlist of ten miRs (miR-7a-2-3p, miR-29c-3p, miR-96-5p, miR-101a-3p, miR-140-5p, miR-146a-5p, miR-146b-5p, miR-340-5p, miR-384-5p, and miR-455-5p) regulated by both cytokines and Givinostat was verified by qRT-PCR. MiR-146a-5p was strongly regulated by cytokines and KDACi and analyzed further. MiR-146a-5p expression was induced by cytokines in rat and human islets. Cytokine-induced miR-146a-5p expression was specific for INS1 and β-TC3 cells, whereas α-TC1 cells exhibited a higher basal expression. Transfection of INS1 cells with miR-146a-5p reduced the activity of NFκB and iNOS promoters, decreased NO production, and decreased protein levels of iNOS and its own direct target TNF receptor associated factor 6 (TRAF6). MiR-146a-5p was elevated in diabetes-prone BB-DP rat pancreas at diabetes onset, suggesting that miR-146a-5p could play a role in type 1 diabetes development. The miR array of cytokine-exposed INS1 cells rescued by KDACi revealed several other miRs potentially involved in cytokine-induced b-cell apoptosis, demonstrating the strength of this approach.
2018-10-01 | GSE117451 | GEO