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Small extracellular vesicle-derived miR-574-5p regulates PGE2-biosynthesis via TLR7/8 in lung cancer.

ABSTRACT: Intercellular communication plays an essential role in lung cancer (LC). One of the major players in cell-cell-communication is small extracellular vesicles (sEV). SEV trigger various biological responses by transporting cellular cargo to target cells. One essential sEV component are microRNAs (miRs), whose transport has recently attracted increasing research interest. We report that prostaglandin E₂ (PGE₂ ), a key inflammatory lipid mediator, specifically induces the sorting of miR-574-5p in sEV of A549 and 2106T cells. We found that sEV-derived miR-574-5p activates Toll-like receptors (TLR) 7/8, thereby decreasing PGE₂ -levels. In contrast, intracellular miR-574-5p induces PGE₂ -biosynthesis. Consequently, the combination of intracellular and sEV-derived miR-574-5p controls PGE₂ -levels via a feedback loop. This was only observed in adeno- but not in squamous cell carcinoma, indicating a cell-specific response to sEV-derived miRs, which might be due to unique tetraspanin compositions. Hence, we describe a novel function of miR-574-5p unique to adenocarcinoma. Intracellular miR-574-5p induces PGE₂ and thus the secretion of sEV-derived miR-574-5p, which in turn decreases PGE₂ -biosynthesis in recipient cells.

SUBMITTER: Donzelli J

PROVIDER: S-EPMC8485338 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Extracellular miR-574-5p Induces Osteoclast Differentiation via TLR 7/8 in Rheumatoid Arthritis.

Project description:Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. Cell-derived small extracellular vesicles (sEV) mediate cell-to-cell communication in the synovial microenvironment by carrying microRNAs (miRs), a class of small non-coding RNAs. Herein, we report that sEV from synovial fluid promote osteoclast differentiation which is attributed to high levels of extracellular miR-574-5p. Moreover, we demonstrate for the first time that enhanced osteoclast maturation is mediated by Toll-like receptor (TLR) 7/8 signaling which is activated by miR-574-5p binding. This is a novel mechanism by which sEV and miRs contribute to RA pathogenesis and indicate that pharmacological inhibition of extracellular miR-574-5p might offer new therapeutic strategies to protect osteoclast-mediated bone destruction in RA.

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Endometrial cell-derived small extracellular vesicle miR-100-5p promotes functions of trophoblast during embryo implantation.

Project description:Communication between maternal uterus and blastocyst occurs in the early stages of pregnancy, and the interaction influences the success of embryo implantation. Whereas small extracellular vesicles (sEVs) play an essential role in mediating intercellular communication in numerous biological processes, their role in embryo implantation during the window of implantation (WOI) remains poorly defined. Here, we report that endometrial epithelial cells (EECs) secrete sEVs during early pregnancy, which affects the trophoblast behaviors (migration, invasion, and proliferation), thus influencing embryo implantation. We show that microRNA (miR)-100-5p, sEVs containing microRNA (miRNA), activates both focal adhesion kinase (FAK) and c-Jun N-terminal kinase (JNK), as well as contributes to trophoblast migration and invasion. Furthermore, our findings indicate that the sEV miR-100-5p promotes angiogenesis during the implantation process. In conclusion, this study reveals a novel mechanism by which EEC-derived sEV miR-100-5p crosstalks with trophoblasts, leading to an enhanced ability for implantation.

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Extracellular vesicles miR-574-5p and miR-181a-5p as prognostic markers in NSCLC patients treated with nivolumab

Project description:Plasma from 245 patients with advanced NSCLC who received nivolumab as second-line therapy was collected and analyzed. EV-miRnome was profiled on 174/245 patients by microarray platform and selected EV-miRs were validated by qPCR. A prognostic model combining EV-miR and clinical variables was built using stepwise Cox regression analysis and tested on an independent patient cohort (71/245). EV-PD-L1 gene copy number was assessed by digital PCR. For 54 patients with disease control, EV-miR changes at best response versus baseline were investigated by microarray and validated by qPCR. EV-miRNome profiling at baseline identified two EV-miR (miR-181a-5p, miR-574-5p) that, combined with performance status, are capable of discriminating patients unlikely from those that are likely to benefit from immunotherapy (median overall survival of 4 months or higher than 9 months, respectively). EV-PD-L1 digital evaluation reported higher baseline copy number in patients at increased mortality risk, without improving the prognostic score. Best response EV-miRNome profiling selected six deregulated EV-miRs (miR19a-3p, miR-20a-5p, miR-142-3p, miR-1260a, miR-1260b, miR-5100) in responding patients. Their longitudinal monitoring highlighted a significant downmodulation already in the first treatment cycles, which lasted more than six months. Grantee: Simona Coco Grantor: Italian Ministry of Health Grant ID: CO-2016-02361470 Grant Title: Exosomal miRNA signature as prognostic marker in advanced non-small cell lung cancer (NSCLC) patients treated with Nivolumab

2024-07-28 | GSE207715 | GEO

MiR-574-5p: A Circulating Marker of Thoracic Aortic Aneurysm.

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| S-EPMC6720007 | biostudies-literature

miR-10a-5p and miR-29b-3p as Extracellular Vesicle-Associated Prostate Cancer Detection Markers.

Project description:Extracellular vesicles (EVs) are shed by many different cell types. Their nucleic acids content offers new opportunities for biomarker research in different solid tumors. The role of EV RNA in prostate cancer (PCa) is still largely unknown. EVs were isolated from different benign and malignant prostate cell lines and blood plasma from patients with PCa (n = 18) and controls with benign prostatic hyperplasia (BPH) (n = 7). Nanoparticle tracking analysis (NTA), Western blot, electron microscopy, and flow cytometry analysis were used for the characterization of EVs. Non-coding RNA expression profiling of PC3 metastatic PCa cells and their EVs was performed by next generation sequencing (NGS). miRNAs differentially expressed in PC3 EVs were validated with qRT-PCR in EVs derived from additional cell lines and patient plasma and from matched tissue samples. 92 miRNAs were enriched and 48 miRNAs were depleted in PC3 EVs compared to PC3 cells, which could be confirmed by qRT-PCR. miR-99b-5p was significantly higher expressed in malignant compared to benign EVs. Furthermore, expression profiling showed miR-10a-5p (p = 0.018) and miR-29b-3p (p = 0.002), but not miR-99b-5p, to be overexpressed in plasma-derived EVs from patients with PCa compared with controls. In the corresponding tissue samples, no significant differences in the miRNA expression could be observed. We thus propose that EV-associated miR-10a-5p and miR-29b-3p could serve as potential new PCa detection markers.

| S-EPMC7017198 | biostudies-literature

HOXA5-miR-574-5p axis promotes adipogenesis and alleviates insulin resistance.

Project description:Differentiation of preadipocytes into functional adipocytes could be a major target for repressing obesity-induced insulin resistance (IR). However, the molecular mechanisms involved in adipogenesis and the development of IR are unclear. We report, for the first time, that miR-574-5p, a novel miRNA, promotes adipogenesis to suppress IR. An increase in the level of miR-574-5p significantly induced the differentiation of preadipocytes into mature adipocytes. Conversely, reduction of miR-574-5p levels blocked the differentiation of preadipocytes in vitro. In a dual-luciferase reporter assay, it was shown that homeobox A5 (HOXA5) promoted the transcription of miR-574-5p to induce the differentiation of preadipocytes. Hdac9, a direct downstream target of miR-574-5p, was involved in the regulation of adipocyte differentiation. The overexpression of miR-574-5p also promoted adipogenesis in subcutaneous fat to alleviate IR in high-fat-diet-fed mice. Additionally, miR-574-5p expression was significantly higher in the subcutaneous adipose tissue of obese patients without type 2 diabetes than in those with type 2 diabetes. There was an increase in HOXA5 expression and a decrease in histone deacetylase 9 (HDAC9) expression in the subcutaneous fat of obese patients without type 2 diabetes. These results suggest that miR-574-5p may be a potential therapeutic target for combating obesity-related IR.

| S-EPMC8693313 | biostudies-literature

Exosomal lipid PI4P regulates small extracellular vesicle secretion by modulating intraluminal vesicle formation.

Project description:Membrane lipids play vital roles in small extracellular vesicle (sEV) biogenesis. However, the function of various lipids in the biogenesis of sEVs is still poorly understood. Phosphoinositolphosphates (PIPs), a group of the most critical lipids in vesicle transport, can undergo rapid conversion in response to a variety of cell signals, which in turn influence the generation of vesicles. Due to the challenge in detecting the low amount of PIP content in biological samples, the function of PIPs in sEVs has been insufficiently investigated. Here, we employed an LC-MS/MS method to detect the levels of PIPs in sEVs. We revealed phosphatidylinositol-4-phosphate (PI4P) was the main PI-monophosphate in macrophage-derived sEVs. The release of sEVs was regulated in a time-dependent manner and correlated with the PI4P level during the lipopolysaccharide (LPS) stimulation. In terms of mechanism, within 10 h of LPS treatment, the LPS-induced production of type I interferon inhibited the expression of PIP-5-kinase-1-gamma, which increased the PI4P content on multivesicular bodies (MVBs) and recruited RAB10, member RAS oncogene family, to promote sEV generation. When LPS stimulation was extended to 24 h, the heat shock protein family A member 5 (HSPA5) expression level was elevated. PI4P interacted with HSPA5 on the Golgi or endoplasmic reticulum away from MVBs, which disrupted the continuous fast sEV release. In conclusion, the present study demonstrated an inducible sEV release model response to LPS treatment. The inducible release may be due to PI4P regulating the generation of intraluminal vesicles secreted as sEVs.

| S-EPMC10076970 | biostudies-literature

miR-574-5p negatively regulates Qki6/7 to impact ?-catenin/Wnt signalling and the development of colorectal cancer.

Project description:ObjectiveDeficiency or reduced expression of signal transduction and activation of RNA family protein Quaking (Qki) is associated with developmental defects in neural and vascular tissues and the development of debilitating human diseases including colorectal cancer (CRC). However, the mechanisms underlying the aberrant downregulation or deficiency of Qki were uncertain.DesignExpression of miR-574-5p, Qki5/6/7/7b splicing variants, ?-catenin and p27(Kip1) was determined in mouse and human CRC cells and tissues to investigate the post-transcriptional regulation of Qki isoforms by miR-574-5p and its impact on ?-catenin/p27(Kip1) signalling, cell cycle progression, proliferation, migration, invasion and tumour growth.ResultsIn the CRC tissues of C57BL/6-Apc(min/+) mice, miR-574-5p was found to be significantly upregulated and negatively correlated with the expression of Qki but positively correlated with the expression of ?-catenin. In mouse and human CRC cells, miR-574-5p was shown to regulate Qki isoforms (Qki6/7 in particular) post-transcriptionally and caused altered expression in ?-catenin and p27(Kip1) , increased proliferation, migration and invasion and decreased differentiation and cell cycle exit. Furthermore, in clinical CRC tissues, miR-574-5p was shown to be greatly upregulated and inversely correlated with the expression of Qkis. Finally, inhibition of miR-574-5p was shown to suppress the growth of tumours in the nude mice.ConclusionsTogether, these novel findings suggest that miR-574-5p is a potent ribo-regulator for Qkis and that aberrant miR-574-5p upregulation can be oncogenic.

| S-EPMC3618686 | biostudies-literature

MiR-574-5p activates human TLR8 to promote autoimmune signaling and lupus.

Project description:Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling and B lymphocytes, and the production of autoantigens. In a transgenic mouse model, the induction of miR-574-5p overexpression is associated with increased secretion of antinuclear and anti-dsDNA antibodies, increased IgG and C3 deposit in the kidney, elevated expression of inflammatory genes in the spleen. In lupus-prone mice, lentivirus-mediated silencing of miR-574-5p significantly ameliorates major symptoms associated with lupus and lupus nephritis. Collectively, these results suggest that the miR-574-5p-hTLR8/mTlr7 signaling is an important axis of immune and inflammatory responses, contributing significantly to the development of lupus and lupus nephritis.

| S-EPMC11000404 | biostudies-literature

hsa_circ_0008234 inhibits the progression of lung adenocarcinoma by sponging miR-574-5p.

Project description:circRNAs are a novel type of noncoding RNA (ncRNA) that have been identified as an important regulator of gene expression and play a part in the progression of various diseases. However, the function of circ_0008234 in lung adenocarcinoma (LUAC) remains unknown. Through the GEO (Gene Expression Omnibus) database, circ_0008234 was first found to be downregulated in LUAC tissues. It could inhibit cell growth and accelerate apoptosis in vitro and in vivo. In terms of its possible mechanism, circ_0008234 mainly was present in the cytoplasm and competed with miR-574-5p to regulate RND3 (Rho family GTPase 3). Our results revealed that circ_0008234 inhibited the progression of LUAC through a competing endogenous RNA (ceRNA)-based mechanism and provided potential biomarkers and therapeutic targets for LUAC treatment.

| S-EPMC8163831 | biostudies-literature

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