Glioma stem cell-derived exosomal miR-944 reduces glioma growth and angiogenesis by inhibiting AKT/ERK signaling.
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SUBMITTER: Jiang J
PROVIDER: S-EPMC8386563 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundCancer stem cells (CSCs), which are involved in cancer initiation and metastasis, could potentially release exosomes that mediate cellular communication by delivering microRNAs (miRNAs). Based on the role of miR-26a in angiogenesis of glioma, our study was performed to investigate whether glioma stem cells (GSCs)-derived exosomes containing miR-26a could exert effects on angiogenesis of microvessel endothelial cells in glioma, in order to provide a new therapeutic RNA vehicle for glioma therapies.MethodsThe expression of miR-26a and PTEN in glioma was quantified and the interaction among miR-26a, PTEN and PI3K/Akt signaling pathway was examined. Next, a series of gain- and loss-of function experiments were conducted to determine the role of miR-26a in angiogenesis of human brain microvascular endothelial cells (HBMECs). Subsequently, HBMECs were exposed to exosomes derived from GSCs with the gain-/loss-of-function of miR-26a. Finally, the effect of exosomal miR-26a on angiogenesis of HBMECs was assessed both in vitro and in vivo.ResultsThe results revealed that PTEN was down-regulated, while miR-26a was up-regulated in glioma. miR-26a activated the PI3K/Akt signaling pathway by targeting PTEN. Restored miR-26a promoted proliferation, migration, tube formation, and angiogenesis of HBMECs in vitro. In addition, GSCs-derived exosomes overexpressing miR-26a contributed to enhanced proliferation and angiogenesis of HBMECs in vitro through inhibition of PTEN. The angiogenic effects of GSCs-derived exosomes overexpressing miR-26a in vivo were consistent with the above-mentioned in vitro findings.ConclusionCollectively, our study demonstrates that GSCs-derived exosomal miR-26a promotes angiogenesis of HBMECs, highlighting an angiogenic role of miR-26a via exosomes.
| S-EPMC6525364 | biostudies-literature
Project description:BackgroundDistraction osteogenesis (DO) is a widely used bone regenerative technique. However, the DO process is slow, and the consolidation phase is long. Therefore, it is of great clinical significance to explore the mechanism of DO, and shorten its duration. Recent studies reported that stem cell exosomes may play an important role in promoting angiogenesis related to DO, but the mechanism remains unclear.MethodsCanine endothelial colony-forming cells (ECFCs) were isolated and cultured, and the expression of THBS1 in canine ECFCs were inhibited using a lentiviral vector. The exosomes secreted by canine ECFCs were isolated and extracted, and the effect of exosomes on the angiogenic activity of Human umbilical vein endothelial cells (HUVECs) was detected by proliferation, migration, and tube formation experiments. WB and qRT-PCR were used to explore the effects and mechanisms of THBS1-mediated ECFC-Exos on HUVECs angiogenesis. Then, a mandibular distraction osteogenesis (MDO) model was established in adult male beagles, and exosomes were injected into the canine peripheral blood. Micro-CT, H&E, Masson, and IHC staining were used to explore the effects and mechanisms of THBS1-mediated ECFC-Exos on angiogenesis and osteogenesis in the DO area.ResultsECFC-Exo accelerated HUVECs proliferation, migration and tube formation, and this ability was enhanced by inhibiting the expression of THBS1 in ECFC-Exo. Using Western blot-mediated detection, we demonstrated that inhibiting THBS1 expression in ECFCs-Exo activated PI3K, AKT, and ERK phosphorylation levels in HUVECs, which promoted VEGF and bFGF expressions. In the DO model of the canine mandible, ECFCs-Exo injected into the peripheral blood aggregated into the DO gap, thus promoting angiogenesis and bone formation in the DO tissue by reducing THBS1 expression in ECFC-Exo.ConclusionOur findings suggested that ECFC-Exos markedly enhances angiogenesis of endothelial cells, and promotes bone healing in canine MDO. Thus, THBS1 plays a crucial role in the ECFC-Exos-mediated regulation of canine MDO angiogenesis and bone remodeling.The translational potential of this articleThis study reveals that the angiogenic promotion via THBS1 suppression in ECFC-Exos may be a promising strategy for shortening the DO duration.
| S-EPMC9513111 | biostudies-literature
Project description:Purpose: Most patients with pancreatic ductal adenocarcinoma (PDAC) have vascular invasion and metastasis, leading to low surgical resection rate and dismal prognosis. Tumor angiogenesis is related to vascular invasion and metastasis. However, anti-angiogenesis therapeutic effects in PDAC are limited. Therefore, it is imperative to explore molecular mechanism of angiogenesis in PDAC. Experimental Design: scRNA-seq data were utilized to delineatetranscriptional profiles of endothelial cells in PDAC. The in vitro and vivo angiogenesis models were used to explore the role of PDAC derived exosomes under hypoxic condition in tumor angiogenesis. Results: Endothelial cells in PDAC had distinct gene expression profiles compared with normal pancreas. The marker genes of endothelial cells in PDAC were enriched for hypoxia and angiogenesis. MiR-30b-5p were significantly enriched in hypoxic PDAC cells derived exosomes, which could be transferred to HUVEC, resulting in the upregulation of miR-30b-5p. Hypoxic PDAC cells derived exosomes could promote tube formation and endothelial cells migration via miR-30b-5p mediated downregulation of gap junction protein GJA1. Moreover, hypoxic PDAC cells derived exosomes increased new microvascular density in vivo. Patients with PDAC had higher levels of total miR-30b-5p and exosomal miR-30b-5p in peripheral blood plasma than healthy subjects. In addition, there were significant correlations for the levels of total miR-30b-5p or exosomal miR-30b-5p between peripheral blood plasma and portal vein plasma. Conclusions: Hypoxic PDAC cells derived exosomal miR-30b-5p promoted angiogenesis by inhibiting GJA1, and miR-30b-5p was a potential diagnostic marker for PDAC.
| S-EPMC8771853 | biostudies-literature
Project description:BackgroundExosomal miR-29b reportedly plays a role during cancer metastasis. However, its exact function and underlying mechanism during pancreatic cancer (PC) have not been investigated.MethodsExosomes from PC cells were prepared and identified. Transmission electron microscopy (TEM) and confocal microscopy were used to examine structural characteristics of the exosomes and verify their internalization by human umbilical vein endothelial cells (HUVECs). The tube formation and migration abilities of HUVECs were detected. VEGF content was assessed by ELISA. GW4869 was used to suppress exosome release. Luciferase reporter assays were performed to verify the predicted interaction of miR-29b with ROBO1 and SRGAP2 mRNA.ResultsExosomal miRNA-29b was differentially expressed in the conditioned medium of PC cells. Exosomes from PC cells were verified by TEM and western blotting. Treatment with the exosomal inhibitor (GW4869) prevented an increase in miR-29b expression and recused the reduced VEGF expression and tube formation and migration abilities of HUVECs cocultured with BxPC3 and AsPC-1 cells that overexpressed miR-29b. Furthermore, the downregulation of ROBO1 and SRGAP2 in cocultured HUVECs was also reduced after additional treatment with GW4869. After incubation with miR-29b exosomes, HUVECs had lower VEGF concentrations and reduced migration and tube formation rates; however, those effects were eliminated by subsequent transfection with the miR-29b inhibitor. Luciferase reporter assays verified the interaction of miR-29b with ROBO1 and SRGAP2. That interaction was also supported by rescue assays showing that overexpression of ROBO1 and SRGAP2 also reduced the antiangiogenic effect of exosomal miR-29b in HUVECs.ConclusionExosomal miR-29b originating from PC cells protected HUVECs from PC cell-induced angiogenesis by attenuating ROBO1 and SRGAP2 expression. Our findings suggest a strategy for treating PC.
| S-EPMC9586796 | biostudies-literature
Project description:Angiogenesis and osteogenesis are tightly coupled during bone modeling and remodeling processes. Here we reported that bone marrow mesenchymal stem cell (BMSC)-derived exosomal miR-29a promotes angiogenesis and osteogenesis in vitro and in vivo. BMSC-derived exosomes (BMSCs-Exos) can be taken up by human umbilical vein endothelial cells (HUVECs) and promote the proliferation, migration, and tube formation of HUVECs. MiRNA-29a level was high in BMSCs-Exos and can be transported into HUVECs to regulate angiogenesis. VASH1 was identified as a direct target of miR-29a, mediating the effects of BMSC-derived exosomal miR-29a on angiogenesis. More interestingly, miR29a-loaded exosomes from engineered BMSCs (miR-29a-loaded BMSCs-Exos) showed a robust ability of promoting angiogenesis and osteogenesis in vivo. Taken together, these findings suggest that BMSC-derived exosomal miR-29a regulates angiogenesis and osteogenesis, and miR-29a-loaded BMSCs-Exos may serve as a potential therapeutic target for osteoporosis.
| S-EPMC7755650 | biostudies-literature
Project description:Infiltration by dendritic cells (DCs) is markedly increased in the infarcted area following myocardial infarction (MI), and DC ablation has been shown to impair angiogenesis in mice post‑MI. Exosomes (EXs) have long been known to act as messengers between cells; however, whether EXs derived from DCs can enhance myocardial angiogenesis post‑MI remains unknown. The aim of the present study was to elucidate whether EXs derived from DCs induce myocardial angiogenesis via paracrine signaling post‑MI. In vitro, suspensions of mouse bone marrow‑derived DCs (BMDCs) were incubated with the supernatant of necrotic or normal cultured HL‑1 myocardial cells (as the MI or control group, respectively) for 24 h. EXs isolated from the supernatant of BMDCs were termed DEXs, which were added to primary cultures of rat cardiac microvascular endothelial cells (CMECs), and angiogenesis was evaluated by measuring tube formation and vascular endothelial growth factor (VEGF) expression. In vivo, different groups of DEXs were injected into the infarcted myocardium of MI model mice. Then, angiogenesis was evaluated by measuring the number of vessels and the expression of VEGF and CD31 in the infarcted myocardium using immunohistochemistry. Moreover, the expression profile of microRNAs (miRNAs or miRs) in splenic DCs of MI model mice was analyzed by Affymetrix miRNA 4.0 chip assays, then certified in DEXs by reverse transcription‑quantitative PCR analysis. Finally, miRNA‑loaded DEXs were used to induce tube formation by CMECs and angiogenesis in MI model mice. It was observed that, compared with the control group, DEXs from the MI group significantly upregulated the expression of VEGF in CMECs, enhanced tube formation by CMECs, and upregulated the expression of VEGF and CD31 in the infarcted myocardium of MI model mice. miR‑494‑3p and miR‑16a‑5p, which are associated with angiogenesis, were significantly upregulated in splenic DCs of MI model mice by Affymetrix miRNA 4.0 chip assays, miR‑494‑3p was significantly upregulated and highly enriched in DEXs from the MI group compared with the control, and DEX‑miR‑494‑3p enhanced tube formation by CMECs and angiogenesis in mice post‑MI. These results suggest that miR‑494‑3p may be secreted from DCs via EXs and promotes angiogenesis post‑MI. These findings indicate a novel DEX‑based approach to the treatment of MI.
| S-EPMC7723512 | biostudies-literature
Project description:Hepatopulmonary syndrome (HPS) is a serious vascular complication in the setting of liver disease. Factors produced by the liver are essential to regulate pulmonary angiogenesis in the pathogenesis of HPS; however, the pathogenic mechanisms of pulmonary angiogenesis are not fully understood. We investigated the role of HPS rat serum exosomes (HEs) and sham-operated rat serum exosomes (SEs) in the regulation of angiogenesis. We found that HEs significantly enhance PMVEC proliferation, migration, and tube formation. We further identified miR-194 was the most notably increased miRNA in HEs compared to SEs. Once released, hepatocyte-derived exosomal miR-194 was internalized by PMVECs, leading to the promotion of PMVEC proliferation, migration, and tube formation through direct targeting of THBS1, STAT1, and LIF. Importantly, the pathogenic role of exosomal miR-194 in initiating angiogenesis was reversed by P53 inhibition, exosome secretion inhibition or miR-194 inhibition. Additionally, high levels of miR-194 were found in serum exosomes and were positively correlated with P(A-a)O2 in HPS patients and rats. Thus, our results highlight that the exosome/miR-194 axis plays a critical pathologic role in pulmonary angiogenesis, representing a new therapeutic target for HPS.
| S-EPMC6838168 | biostudies-literature
Project description:BackgroundExosomes are small vesicles containing a wide range of functional proteins, mRNA and miRNA. Exosomal miRNAs from cancer cells play crucial roles in mediating cell-cell communication and tumor-microenvironment cross talk, specifically in enabling metastasis and promoting angiogenesis. We focused on miR-9 that was identified as a tumor suppressor previously in nasopharyngeal carcinoma (NPC) tumorigenesis.MethodsDifferential centrifugation, transmission electron microscopy and nanoparticle tracking analysis were used to isolate and identify exosomes. Quantitative PCR and western blotting analysis were used to detect miR-9, pri-miR-9, CD63, TSG101, MDK, P70S6K P-Ser424 and PDK1 P-Ser241 expression. Laser confocal microscopy was used to trace exosomal miR-9 secreted by NPC cells into HUVECs. The effect of exosomal miR-9 on cell migration and tube formation of HUVECs in vivo and vitro was assessed by using migration assay, tube formation assay and matrigel plug assay, respectively. Bioinformatics analysis and luciferase reporter assay were utilized to confirm the binding of exosomal miR-9 to the 3'untranslated region (3'-UTR) of MDK, while Phosphorylation Array was performed to identify AKT Pathway in HUVECs treated with exosomal miR-9. Furthermore, Immunohistochemistry (IHC) and in situ hybridization (ISH) was used to detected miR-9, CD31 and MDK expression in human NPC tumor samples.ResultsNPC cells transfected with miR-9-overexpressing lentivirus, released miR-9 in exosomes. Exosomal miR-9 directly suppressed its target gene - MDK in endothelial cells. Mechanistic analyses revealed that exosomal miR-9 from NPC cells inhibited endothelial tube formation and migration by targeting MDK and regulating PDK/AKT signaling pathway. Additionally, the level of MDK was upregulated in NPC tumor samples and was positively correlated with microvessel density. Notably, the level of exosomal miR-9 was positively correlated with overall survival, and MDK overexpression was positively associated with poor prognosis in NPC patients, suggesting the clinical relevance and prognostic value of exosomal miR-9 and MDK.ConclusionsTaken together, our data identify an extracellular anti-angiogenic role for tumor-derived, exosome-associated miR-9 in NPC tumorigenesis and prompt further investigation into exosome-based therapies for cancer treatment.
| S-EPMC6044044 | biostudies-literature
Project description:BackgroundGlioma is the most frequent and lethal primary brain malignancy. Amounting evidence has highlighted the importance of exosomal microRNAs (miRNAs or miRs) in this malignancy. This study aimed to investigate the regulatory role of exosomal miR-148a-3p in glioma.MethodsBioinformatics analysis was firstly used to predict the target genes of miR-148a-3p. Exosomes were then extracted from normal human astrocytes and glioma cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was applied to determine the expression patterns of miR-148a-3p and ERBB receptor feedback inhibitor 1 (ERRFI1). Dual-luciferase reporter gene assay was applied to verify the direct binding between miR-148a-3p and ERRFI1. Cell counting kit-8 and tube formation assays were further conducted to assess the proliferation and angiogenic properties of human umbilical vein endothelial cells (HUVECs) in the co-culture system with exosomes. Lastly, glioma tumor models were established in BALB/c nude mice to study the role of exosomal miR-148a-3p in vivo.ResultsmiR-148a-3p was highly expressed, while ERRFI1 was poorly expressed in glioma. miR-148a-3p was found to be enriched in glioma cells-derived exosomes and could be transferred to HUVECs via exosomes to promote their proliferation and angiogenesis. ERRFI1 was identified as a target gene of miR-148a-3p. In addition, miR-148a-3p activated the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signaling pathway by inhibiting ERRFI1. In the co-culture system, our data demonstrated that glioma cells-derived exosomal miR-148a-3p down-regulated ERRFI1 and activated the EGFR/MAPK signaling pathway, so as to promote cell proliferation and angiogenesis. In vivo experimentation further demonstrated that this mechanism was responsible for the promotive role of exosomal miR-148a-3p in tumorigenesis and angiogenesis.ConclusionTaken together, glioma-derived exosomal miR-148a-3p promoted tumor angiogenesis through activation of the EGFR/MAPK signaling pathway by ERRFI1 inhibition.
| S-EPMC7590612 | biostudies-literature
Project description:BackgroundGlioma is a brain tumor with high morbidity and mortality rates. Understanding its molecular pathogenesis can provide targets and therapeutic strategies for glioma treatment. miR-338-3p represses tumor growth in several cancers, including glioma. Thus, this study aimed to identify the regulatory effects of miR-338-3p/phosphoinositide 3-kinase (PI3K)/Akt/thrombospondins 1 (THBS1) on glioma progression.Materials and methodsQuantitative reverse transcription polymerase chain reaction and western blotting were performed to evaluate the levels of miR-338-3p, THBS1, and PI3K/Akt phosphorylation-related proteins. TargetScan software predicted that miR-338-3p targeted THBS1. This was confirmed by performing the dual-luciferase assay. Wound-healing and cell-counting-kit-8 experiments were performed to analyze how THBS1 and miR-338-3p affect the ability of glioma cells to migrate and proliferate. The effect of miR-338-3p on tumorigenicity in mice was also analyzed.ResultsmiR-338-3p downregulation was observed in gliomas, whereas THBS1 showed the opposite trend. By suppressing the PI3K/Akt signaling pathway activation, miR-338-3p overregulated the ability of glioma cells to migrate and proliferate in vitro. Additionally, miR-338-3p inhibited the development of glioma tumors in vivo. Moreover, miR-338-3p directly targeted THBS1. THBS1 overexpression promoted glioma cell migration and proliferation by increasing PI3K/Akt phosphorylation. Nonetheless, miR-338-3p overregulation alleviated the effects of THBS1 overexpression.ConclusionThe miR-338-3p/PI3K/Akt/THBS1 regulatory axis can modulate the progression of glioma cell proliferation and migration; thus, it can be considered a therapeutic biomarker.
| S-EPMC10807173 | biostudies-literature