RETRACTED: miR-135b Delivered by Gastric Tumor Exosomes Inhibits FOXO1 Expression in Endothelial Cells and Promotes Angiogenesis
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ABSTRACT:
SUBMITTER: Bai M
PROVIDER: S-EPMC6822229 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC6171076 | biostudies-literature
Project description:Papillary thyroid cancer (PTC) is the most common type of thyroid cancer, and angiogenesis plays critical roles in its recurrence and metastasis. In this study, we investigated the effects of hypoxia-induced exosomal microRNA-181 (miR-181a) from PTC on tumor growth and angiogenesis. Thyroid-cancer-related differentially expressed miR-181a was identified by microarray-based analysis in the Gene Expression Omnibus (GEO) database. We validated that miR-181a was highly expressed in PTC cells and even more so in cells cultured under hypoxic conditions, which also augmented exosome secretion from PTC cells. Exosomes extracted from PTC cells with manipulated miR-181a and mixed-lineage leukemia 3 (MLL3) were subjected to normoxic or hypoxic conditions. Human umbilical vein endothelial cells (HUVECs) were transfected with miR-181a inhibitor/mimic or small interfering RNA (siRNA)-MLL3 or treated with exosomes from hypoxic PTC cells. Hypoxic exosomal miR-181a delivery promoted proliferation and capillary-like network formation in HUVECs. Mechanistically, miR-181a targeted and inhibited MLL3. Furthermore, miR-181a downregulated DACT2 and upregulated YAP and vascular endothelial growth factor (VEGF). Further, hypoxic exosomal miR-181a induced angiogenesis and tumor growth in vivo, which was reversed by hypoxic exosomal miR-181a inhibitor. In conclusion, exosomal miR-181a from hypoxic PTC cells promotes tumor angiogenesis and growth through MLL3 and DACT2 downregulation, as well as VEGF upregulation.
| S-EPMC8054101 | biostudies-literature
Project description:Exosomes derived from cancer cells have emerged as important mediators of malignant phenotypes of tumors, being involved in the transmission of biological signals between cells. Herein, we intended to clarify the role of exosome-mediated transfer of oncogenic microRNA-27a (miR-27a) in angiogenesis of renal clear cell carcinoma (RCCC). Through bioinformatics analysis, we identified the differentially expressed genes of RCCC and predicted miRNAs targeting SFRP1. We manipulated the expression of miR-27a and/or SFRP1 in RCCC cells to explore their roles in angiogenesis through Cell Counting Kit-8 (CCK-8), Transwell, and Matrigel tubule formation assays. miR-27a loaded in exosomes was overexpressed and downregulated in vitro and in vivo to verify its effect on angiogenesis. SFRP1 was poorly expressed and miR-27a was highly expressed in RCCC tissues, showing a negative correlation. Dual-luciferase assay verified that miR-27a targeted and downregulated SFRP1 expression. Notably, miR-27a enhanced angiogenesis by downregulating SFRP1 expression. miR-27a-loaded exosomes can be delivered from RCCC cells to human umbilical vein endothelial cells (HUVECs). In vitro and in vivo experiments substantiated that miR-27a-loaded exosomes from RCCC cells repressed SFRP1, augmenting the viability, migration, and angiogenesis of RCCC cells. Together, RCCC-derived miR-27a-loaded exosomes inhibit SFRP1 expression and accelerate tumor angiogenesis in RCCC.
| S-EPMC7941030 | biostudies-literature
Project description:Recent evidence has suggested an important role of miRNAs in liver biology and diseases, although the implication of miRNAs in cholangiocarcinoma remains to be defined further. This study was designed to examine the biological function and molecular mechanism of miR-101 in cholangiocarcinogenesis and tumor progression. In situ hybridization and quantitative RT-PCR were performed to determine the expression of miR-101 in human cholangiocarcinoma tissues and cell lines. Compared with noncancerous biliary epithelial cells, the expression of miR-101 is decreased in 43.5% of human cholangiocarcinoma specimens and in all three cholangiocarcinoma cell lines used in this study. Forced overexpression of miR-101 significantly inhibited cholangiocarcinoma growth in severe combined immunodeficiency mice. miR-101-overexpressed xenograft tumor tissues showed decreased capillary densities and decreased levels of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). The VEGF and COX-2 mRNAs were identified as the bona fide targets of miR-101 in cholangiocarcinoma cells by both computational analysis and experimental assays. miR-101 inhibits cholangiocarcinoma angiogenesis by direct targeting of VEGF mRNA 3'untranslated region and by repression of VEGF gene transcription through inhibition of COX-2. This study established a novel tumor-suppressor role of miR-101 in cholangiocarcinoma and it suggests the possibility of targeting miR-101 and related signaling pathways for future therapy.
| S-EPMC3644734 | biostudies-literature
Project description:The study of bone marrow stromal cells (BMSCs) and the exosomes they secrete is considered promising for cancer therapy. However, little is known about the effect of donor age on BMSCs. In the present study, we investigated the therapeutic potential of BMSC exosomes derived from donors of different ages using an in vivo model of hypoxic bone marrow in multiple myeloma (MM). We found that donor age was strongly related to senescent changes in BMSCs. Exosomes derived from young BMSCs significantly inhibited MM-induced angiogenesis in Matrigel plugs. The exosomal microRNA (miRNA) expression profile was different between young and older BMSCs, despite similarities in the size and quantity of exosomes. Of note was the observation that the antiangiogenic effect of older BMSCs was enhanced by direct transfection of miR-340 that was preferentially expressed in exosomes derived from young BMSCs. We found that miR-340 inhibited angiogenesis via the hepatocyte growth factor/c-MET (HGF/c-MET) signaling pathway in endothelial cells. Our data provide new insights into exosome-based cancer therapy by modification of BMSC-derived exosomes.
| S-EPMC5727805 | biostudies-literature
Project description:BackgroundCircular RNAs (circRNAs) are endogenous noncoding RNAs that play vital roles in many biological processes, particularly in human cancer. Recent studies indicate that circRNAs play an important role in tumor progression through exosomes. However, the specific functions of gastric cancer-derived exosomes and the role of circSTAU2 in gastric cancer (GC) remain largely unknown.MethodsDifferentially expressed circRNAs in GC were identified by circRNA microarrays analysis and quantitative real-time polymerase chain reaction (qRT-PCR). The role of circSTAU2 in GC was verified by circSTAU2 knockdown and overexpression with functional assays both in vitro and in vivo. Fluorescence in situ hybridization (FISH), immunofluorescence, RNA immunoprecipitation (RIP), dual-luciferase reporter assay, qRT-PCR and Western blot were adopted to evaluate the expression and regulatory mechanism of MBNL1, circSTAU2, miR-589 and CAPZA1. Furthermore, the role of exosomes was demonstrated by transmission electron microscopy and nano-sight particle tracking analysis.ResultsCircSTAU2, mainly localized in the cytoplasm, was significantly downregulated in GC. CircSTAU2 overexpression inhibited GC cell proliferation, invasion and migration both in vitro and in vivo, while circSTAU2 knockdown had the inverse effect. CircSTAU2 could be wrapped in exosomes and delivered to recipient cells, and functioned as a sponge for miR-589 to relieve its inhibitory effect on CAPZA1, thus inhibiting GC progression. Furthermore, MBNL1 acted as the upstream RNA-binding protein of circSTAU2 and significantly influenced the circularization and expression of circSTAU2.ConclusionExosome-delivered circSTAU2 may act as a tumor suppressor that restrains GC progression via miR-589/CAPZA1 axis, which demonstrates a potential therapeutic target for GC.
| S-EPMC9832994 | biostudies-literature
Project description:Chemotherapy has substantially improved gastric cancer (GC) patient outcomes in the past decades. However, the development of chemotherapy resistance has become the major cause of treatment failure. Although numerous molecules have been implicated in GC chemoresistance, its pathological mechanisms are still unclear. Here, we found that integrin subunit alpha 2 (ITGA2) is upregulated in chemoresistant GC cells and that increased ITGA2 levels correlated with the poor prognosis of GC patients who received chemotherapy. ITGA2 overexpression led to elevated chemotherapy resistance and drug-induced apoptosis inhibition in GC cells. ITGA2 knockdown resulted in restored chemosensitivity and increased apoptosis in chemoresistant GC cells both in vitro and in vivo. NanoString analysis revealed a unique signature of deregulated pathway expression in GC cells after ITGA2 silencing. The MAPK/ERK pathway and epithelial-mesenchymal transition (EMT) were found to be downregulated after ITGA2 knockdown. miR-135b-5p was identified as a direct upstream regulator of ITGA2. miR-135b-5p overexpression reduced chemoresistance and induced apoptosis in GC cells and attenuated ITGA2-induced chemoresistance and antiapoptotic effects by inhibiting MAPK signaling and EMT. In conclusion, this study underscored the role and mechanism of ITGA2 in GC and suggested the novel miR-135b-5p/ITGA2 axis as an epigenetic cause of chemoresistance with diagnostic and therapeutic implications.
| S-EPMC7082357 | biostudies-literature
Project description:BackgroundAngiogenesis is important for the progression of gastric cancer (GC). Y-box binding protein 1 (YB-1) predicts advanced disease and indicates neovasculature formation in GC tissues, while the related mechanisms remain elusive. Exosomes mediate intercellular communications via transferring various molecules including proteins, lipids, mRNAs, and microRNAs, while the cargos of GC exosomes and the related mechanisms in GC angiogenesis were rarely reported except for several microRNAs.MethodsIn this study, human umbilical vein endothelial cells (HUVECs) were, respectively, treated by the exosomes isolated from the YB-1 transfected and the control SGC-7901 cells (SGC-7901-OE-Exo and SGC-7901-NC-Exo), and their apoptosis, proliferation, migration, invasion, and angiogenesis were, sequentially, compared. The levels of angiogenic factors including VEGF, Ang-1, MMP-9 and IL-8 in the exosome-treated HUVECs and the GC-derived exosomes were, separately, detected using PCR and Western blotting as well as RNA sequencing assays.ResultsWe observed the consistent level of YB-1 in the exosomes and their originated GC cells, and the internalization of exosomes into HUVECs. Comparing with SGC-7901-NC-Exo, SGC-7901-OE-Exo significantly inhibited the apoptosis but promoted the proliferation, migration, invasion, and angiogenesis of HUVECs, within which the increased mRNA and protein levels of VEGF, Ang-1, MMP-9 and IL-8 were demonstrated. Meanwhile, mRNA levels of VEGF, Ang-1, MMP-9 and IL-8 showed no significant difference between SGC-7901-NC-Exo and SGC-7901-OE-Exo, although statistically higher mRNA of YB-1 was detected in the SGC-7901-OE-Exo.ConclusionsOur findings illustrate YB-1 as the key component of exosome to promote GC angiogenesis by upregulating specific angiogenic factors in the exosome-treated endothelial cells but not in the exosomes themselves.
| S-EPMC7557103 | biostudies-literature
Project description:Exosomes are small endosome-derived vesicles containing a wide range of functional proteins, mRNA, and miRNA. Exosomal miRNA from cancer cells helps modulate the microenvironment. In multiple myeloma (MM), the massive proliferation of malignant plasma cells causes hypoxia. To date, the majority of in vitro hypoxia studies of cancer cells have used acute hypoxic exposure (3-24 hours). Thus, we attempted to clarify the role of MM-derived exosomes in hypoxic bone marrow by using MM cells grown continuously in vitro under chronic hypoxia (hypoxia-resistant MM [HR-MM] cells). The HR-MM cells produced more exosomes than the parental cells under normoxia or acute hypoxia conditions, and miR-135b was significantly upregulated in exosomes from HR-MM cells. Exosomal miR-135b directly suppressed its target factor-inhibiting hypoxia-inducible factor 1 (FIH-1) in endothelial cells. Finally, exosomal miR-135b from HR-MM cells enhanced endothelial tube formation under hypoxia via the HIF-FIH signaling pathway. This in vitro HR myeloma cell model will be useful for investigating MM cell-endothelial cell interactions under hypoxic conditions, which may mimic the in vivo bone marrow microenvironment. Although tumor angiogenesis is regulated by various factors, exosomal miR-135b may be a target for controlling MM angiogenesis.
| S-EPMC4263983 | biostudies-literature
Project description:Injury and dysfunction of endothelial cells (ECs) are closely related to the pathogenesis of steroid-induced osteonecrosis of the femoral head (ONFH), while MicroRNAs (miRNAs) play an essential role in the processes. Extracorporeal shockwave treatment (ESWT) has been used in the non-invasive treatment of various diseases including musculoskeletal and vascular disorders. In particular, ESWT with low energy levels showed a beneficial effect in ischemic tissues. However, there has been no comprehensive assessment of the effect of ESWT and miRNAs on steroid-induced ONFH. In the present study, we investigated the role and mechanism of ESWT and miRNAs both in vitro and in vivo. Using a steroid-induced ONFH rat model, we found that ESWT significantly enhances proliferation and angiogenesis as well as alleviates apoptosis. In two types of ECs, ESWT can promote cell proliferation and migration, enhance angiogenesis, and inhibit apoptosis. Notably, our study demonstrates that miR-135b is downregulated and modulated forkhead box protein O1 (FOXO1) in ECs treated with dexamethasone. Remarkably, both miR-135b knockdown and FOXO1 overexpression reversed the beneficial effect of ESWT on ECs. Additionally, our data suggest that ESWT activates the FOXO1-related pathway to impact proliferation, apoptosis, and angiogenesis. Taken together, this study indicates that ESWT relieves endothelial injury and dysfunction in steroid-induced ONFH via miR-135b targeting FOXO1.
| S-EPMC8791199 | biostudies-literature