The Activation of Mesenchymal Stem Cells by Glioblastoma Microvesicles Alters Their Exosomal Secretion of miR-100-5p, miR-9-5p and let-7d-5p.
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ABSTRACT:
SUBMITTER: Garnier D
PROVIDER: S-EPMC8773192 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cervical cancer screening through detection and treatment of high-grade cervical intraepithelial neoplasia (CIN) is most successful in cancer prevention. However, the accuracy of the current cervical cancer screening tests is still low. The aim of this study was to develop a more accurate method based on circulating exosomal miRNAs. The miRNA sequencing was performed to identify candidate exosomal miRNAs as diagnostic biomarkers in 121 plasma samples from healthy volunteers, cervical carcinoma patients, and CIN patients. A panel with eight differentially expressed exosomal miRNAs was identified to distinguish patients in the CIN II+ group (including advanced CIN II patients) from those in the CIN I- group (including CIN I patients and healthy volunteers). Let-7d-3p and miR-30d-5p showed significant difference between cervical tumors and adjacent normal tissues (P < 0.005), exhibited a consistent trend in plasma samples, and were further validated in 203 independent plasma samples. Integrating these two miRNAs yielded an AUC value of 0.828 to distinguish patients in CIN II+ group from those in CIN I- group. Further integrating them into a cytological test-based model resulted in a higher AUC of 0.887, while the AUC value based on the cytological test alone was 0.766. In summary, plasma exosomal miR-30d-5p and let-7d-3p are valuable diagnostic biomarkers for non-invasive screening of cervical cancer and its precursors. Further validation using large sample sizes is required for clinical diagnosis.
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Project description:BackgroundIdiopathic Pulmonary Fibrosis (IPF) is a degenerative interstitial lung disease with both a poor prognosis and quality of life once the diagnosis is made. In the last decade many features of the disease have been investigated to better understand the pathological steps that lead to the onset of the disease and, moreover, different types of biomarkers have been tested to find valid diagnostic, prognostic and therapy response predictive ones. In the complexity of IPF, microRNA (miRNAs) biomarker investigation seems to be promising.MethodsWe analysed the expression of five exosomal miRNAs supposed to have a role in the pathogenesis of the disease from serum of a group of IPF patients (n = 61) and we compared it with the expression of the same miRNAs in a group of healthy controls (n = 15).ResultsIn the current study what emerged is let-7d down-regulation and, unexpectedly, miR-16 significant down-regulation. Moreover, through a cross-sectional analysis, a clustering of the expression of miR-16, miR-21 and miR-26a was found.ConclusionsThese findings could help the individuation of previously unknown key players in the pathophysiology of IPF and, most interestingly, more specific targets for the development of effective medications.
| S-EPMC8176704 | biostudies-literature
Project description:AimExosomal miRNAs derived from glioblastoma stem cells (GSCs) are important mediators of immunosuppressive microenvironment formation in glioblastoma multiform (GBM), especially in M2-like polarization of tumor-associated macrophages (TAMs). However, the exact mechanisms by which GSCs-derived exosomes (GSCs-exo) facilitate the remodeling of the immunosuppressive microenvironment of GBM have not been elucidated.MethodsTransmission electron microscopy (TME) and nanoparticle tracking analysis (NTA) were applied to verify the existence of GSCs-derived exosomes. Sphere formation assays, flow cytometry, and tumor xenograft transplantation assays were performed to identify the exact roles of exosomal miR-6733-5p. Then, the mechanisms of miR-6733-5p and its downstream target gene regulating crosstalk between GSCs cells and M2 macrophages were further investigated.ResultsGSCs-derived exosomal miR-6733-5p induce macrophage M2 polarization of TAMs by positively targeting IGF2BP3 to activate the AKT signaling pathway, which further facilitates the self-renewal and stemness of GSCs.ConclusionGSCs secrete miR-6733-5p-rich exosomes to induce M2-like polarization of macrophages, as well as enhance GSCs stemness and promote malignant behaviors of GBM through IGF2BP3 activated AKT pathway. Targeting GSCs exosomal miR-6733-5p may provide a potential new strategy against GBM.
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Project description:Exosomes derived from lung cancer cells confer cisplatin (DDP) resistance to other cancer cells. However, the underlying mechanism is still unknown. A549 resistance to DDP (A549/DDP) was established. Microarray was used to analyze microRNA (miRNA) expression profiles of A549 cells, A549/DDP cells, A549 exosomes, and A549/DDP exosomes. There was a strong correlation of miRNA profiles between exosomes and their maternal cells. A total of 11 miRNAs were significantly upregulated both in A549/DDP cells compared with A549 cells and in exosomes derived from A549/DDP cells in contrast to exosomes from A549 cells. A total of 31 downregulated miRNAs were also observed. miR-100-5p was the most prominent decreased miRNA in DDP-resistant exosomes compared with the corresponding sensitive ones. Downregulated miR-100-5p was proved to be involved in DDP resistance in A549 cells, and mammalian target of rapamycin (mTOR) expression was reverse regulated by miR-100-5p. Exosomes confer recipient cells' resistance to DDP in an exosomal miR-100-5p-dependent manner with mTOR as its potential target both in vitro and in vivo. Exosomes from DDP-resistant lung cancer cells A549 can alter other lung cancer cells' sensitivity to DDP in exosomal miR-100-5p-dependent manner. Our study provides new insights into the molecular mechanism of DDP resistance in lung cancer.
| S-EPMC5439933 | biostudies-literature
Project description:Cancer-induced bone pain (CIBP) is the pain caused by metastasis of malignant tumors to the bone, accounting for more than half of all chronic cancer pain, which seriously affects the quality of life among tumor patients. Up to 40% of patients with advanced lung cancer suffer from CIBP. MicroRNA (miRNA) transfers between cells through exosomes, mediates cell-to-cell communication, and performs various biological functions. Studies have shown that miRNAs secreted by cancer can modify the tumor microenvironment, but whether exosome-mediated miRNA transfer plays a role in CIBP is still unknown. In this study, the expression levels of 15 miRNAs in exosomes derived A549 cells and 18 miRNAs in exosomes derived NCI-H1299 cells were significantly up-regulated, and qRT-PCR further confirmed that the level of let-7d-5p was increased most considerably. In vitro, exosomal let-7d-5p (EXO let-7d-5p) can be taken up by dorsal root ganglion (DRG) neurons and inhibit the protein level of the target gene opioid receptor mu 1 (OPRM1). EXO let-7d-5p was further confirmed to be involved in the generation and maintenance of CIBP in vivo. Our findings clarify the molecular mechanism of CIBP caused by the inhibition of OPRM1 by EXO let-7d-5p, providing new clues and intervention targets for the prevention and treatment of CIBP.
| S-EPMC8188355 | biostudies-literature
Project description:Background: Circulating exosomal miRNAs are potential non-invasive biomarkers for colorectal cancer. The present study aimed to validate the novel sensitive and specific exosomal miRNA biomarkers for diagnosing colorectal cancer (CRC). Patients and Methods: Exosomes isolated from the serum of CRC patients and healthy donors by ultracentrifugation were characterized using TEM, qNano, and immunoblotting. The exosomes from 2 healthy donors and 4 CRC patients were subjected to RNA isolation and miRNA sequencing. The differently expressed miRNAs from 165 primary CRC patients and 153 healthy donors were substantiated by RT-qPCR. Results: The RNA-sequence data analysis revealed that 29 exosomal miRNAs (20 downregulated and 9 upregulated) with >1.5-fold difference between CRC patients and healthy donors were selected. The serum exosomal miR-99b-5p and miR-150-5p levels were significantly downregulated in CRC patients as compared to healthy donors (p < 0.0001 and p < 0.0001, respectively) and benign disease (p = 0.009 and p < 0.0001, respectively). The expression levels of exosomal miR-99b-5p and miR-150-5p were significantly decreased in early CRC patients as compared to healthy donors (p < 0.0001 and p < 0.0001, respectively). The expression levels of exosomal miR-99b-5p and miR-150-5p were significantly increased postoperatively (p = 0.0058 and p < 0.0001, respectively). Conclusions: The present study demonstrated that serum exosomal miRNAs are promising, sensitive, specific, and non-invasive diagnostic biomarkers for CRC. Impact: This is the first study to specifically identify exosomal miR-99b-5p and miR-150-5p associated with CRC. This study, therefore, might deepen the understanding of tumor-derived exosomes for CRC diagnosis.
| S-EPMC6842995 | biostudies-literature
Project description:BackgroundNontraumatic osteonecrosis of the femoral head (NONFH) is a common, progressive, and refractory orthopaedic disease. Decreased osteogenesis and angiogenesis are considered the main factors in the pathogenesis of NONFH. We aimed to figure out whether exosomes and exosomal miRNA from necrotic bone tissues of patients with NONFH are involved in the pathogenesis of NONFH and reveal the underlying mechanisms.MethodsRT-PCR and western blotting (WB) were used to detect the expression of osteogenic, adipogenic, and angiogenic markers. ALP staining and Alizarin Red S (ARS) staining were used to evaluate osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). Oil Red O staining was performed to assess the adipocyte deposition. A tube formation assay was used to study angiogenesis of human umbilical vascular endothelial cells (HUVECs). H&E staining and immunohistochemistry (IHC) staining were used to detect the effect of the NONFH exosomes in vivo. MicroRNA sequencing was conducted to identify potential regulators in the NONFH exosomes. The target relationship between miR-100-5p and BMPR2 was predicted and confirmed by a dual luciferase reporter assay and WB.ResultsThe NONFH exosomes reduced the osteogenic differentiation of hBMSCs and angiogenesis of HUVECs. In addition, the injection of the NONFH exosomes caused thinning and disruption of bone trabeculae in the femoral heads of rats. MiR-100-5p expression was upregulated in the NONFH exosomes and inhibited the osteogenesis of hBMSCs and angiogenesis of HUVECs by targeting BMPR2 and suppressing the BMPR2/SMAD1/5/9 signalling pathway. Silencing miR-100-5p expression rescued the reduction in osteogenesis and angiogenesis caused by the NONFH exosomes by activating the BMPR2/SMAD1/5/9 signalling pathway.ConclusionThe NONFH exosomal miR-100-5p can lead to NONFH-like damage by targeting BMPR2 and suppressing the BMPR2/SMAD1/5/9 signalling pathway, which may be involved in the pathophysiological mechanisms of nontraumatic osteonecrosis of the femoral head (NONFH).
| S-EPMC8278698 | biostudies-literature
Project description:BACKGROUND:The "nonclassic" apparent mineralocorticoid excess (NC-AME) has been identified in approximately 7% of general population. This phenotype is characterized by low plasma renin activity (PRA), high serum cortisol (F) to cortisone (E) ratio, low cortisone, high Fractional Excretion of potassium (FEK) and normal-elevated systolic blood pressure (SBP). An early detection and/or identification of novel biomarkers of this phenotype could avoid the progression or future complications leading to arterial hypertension. Isolation of extracellular vesicles, such as exosomes, in specific biofluids support the identification of tissue-specific RNA and miRNA, which may be useful as novel biomarkers. Our aim was to identify miRNAs within urinary exosomes associated to the NC-AME phenotype. METHODS:We perform a cross-sectional study in a primary care cohort of 127 Chilean subjects. We measured BP, serum cortisol, cortisone, aldosterone, PRA. According to the previous reported, a subgroup of subjects was classified as NC-AME (n?=?10). Urinary exosomes were isolated and miRNA cargo was sequenced by Illumina-NextSeq-500. RESULTS:We found that NC-AME subjects had lower cortisone (p?<?0.0001), higher F/E ratio (p?<?0.0001), lower serum potassium (p?=?0.009) and higher FEK 24 h (p?=?0.03) than controls. We found miR-204-5p (fold-change?=?0.115; p 0.001) and miR-192-5p (fold-change?=?0.246; p 0.03) are both significantly downregulated in NC-AME. miR-192-5p expression was correlated with PRA (r?=?0.45; p 0.028) and miR-204-5p expression with SBP (r?=?-?0.48, p 0.027) and F/E ratio (r?=?-?0.48; p 0.026). CONCLUSIONS:These findings could support a potential role of these miRNAs as regulators and novel biomarkers of the NC-AME phenotype.
| S-EPMC6880399 | biostudies-literature
Project description:Malignant mesothelioma (MM) is an asbestos-induced cancer arising on the mesothelial surface of organ cavities. MM is essentially incurable without a means of early diagnosis and no successful standard of care. These facts indicate a deep chasm of knowledge that needs to be filled. Our group recently delved into MM tumor biology from the perspective of exosome-contained microRNAs (miRNAs). We discovered that the most abundant miRNAs in MM cancer exosomes were tumor suppressors, particularly miR-16-5p. This observation lead us to hypothesize that MM cells preferentially secreted tumor-suppressor miRNAs via exosomes. Through separate avenues of potential therapeutic advance, we embarked on an innovative strategy to kill MM tumor cells. We employed small molecule inhibitors to block exosome secretion, thereby reducing miR-16-5p exosome loss and replenishing cellular miR-16-5p leading to reduced tumorigenic capacity and miR-16-5p target oncoproteins CCND1 and BCL2. Additionally, we force-fed MM tumor exosomes back to MM tumor cells, which led to cell death, and a reduction in the same oncoproteins. We recapitulated these results with direct transfection of miR-16-5p, confirmed that this is a cancer-cell specific effect, and elucidated a part of the miR-16-5p mechanism of exosome loading.
| S-EPMC6690928 | biostudies-literature
Project description:BackgroundThe strain parameters of Real-Time Three-Dimensional Spot Tracking Echocardiography (RT3D-STE) are GLS, GAS, GRS, and GCS, while each index can significantly diagnose Acute Myocardial Infarction (AMI) patients, but none of them can distinguish between NSTEMI and STEMI. MicroRNAs (miRNAs) play essential roles in Acute Myocardial Infarction (AMI), but little is known about the value of exosome miRNA combined with Real-Time Three-Dimensional Spot Tracking Echocardiography (RT3D-STE) between ST-segment Elevation Myocardial Infarction (STEMI) and Non-ST-segment Elevation Myocardial Infarction (NSTEMI).AimTo estimate the exosomal miRNAs related to strain parameters of RT3D-STE as biomarkers for early detection of STEMI and NSTEMI.MethodsThe present study collected plasma samples from thirty-four (34) patients with AMI (including STEMI and NSTEMI) and employed high-throughput sequence technology and real-time quantitative polymerase chain reaction (RT-qPCR) to identify the differentially expressed miRNAs. The Pearson correlation coefficient is used to measure the strength of a linear association between differentially expressed miRNAs and strain parameters of RT3D-STE.ResultsTwenty-eight (28) differentially expressed exosomal miRNAs were universally identified between STEMI, NSTEM, and normal groups. Among them, there are 10 miRNAs (miR-152-5p, miR-3681-5p, miR-193a-5p, miR-193b-5p miR-345-5p, miR-125a-5p, miR-365a-3p, miR-4520-2-3p, hsa-miR-193b-3p and hsa-miR-5579-5p) with a Pearson correlation greater than 0.6 with RT3D-STE strain parameters. Especially, miR-152-5p and miR-3681-5p showed the most significant correlation with RT3D-STE strain parameters. Target genes of these 10 miRNAs are analyzed for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways enrichment, and they were found to be mainly involved in the cellular metabolism processes and HIF-1 signaling pathway. RT-qPCR verified the significant differential expression of miR-152-5p and miR-3681-5p between STEMI and NSTEM groups.ConclusionRT3D-STE and exosome miRNAs can be used as a hierarchical diagnostic system in AMI. If the RT3D-STE is abnormal, the exosome miRNAs can be detected again to obtain more detailed and accurate diagnostic results between STEMI and NSTEM groups. Exosomal miR-152-5p and miR-3681-5p may serve as potential biomarkers for ST-segment elevation myocardial infarction.
| S-EPMC9243048 | biostudies-literature