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1.
Medicine (Baltimore) ; 98(41): e17478, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593110

RESUMO

Exosomes are nanometer-sized vesicles with intercellular communication functions, and their encapsulated proteins may participate in the pathological process of neurodegenerative disorders. The aim of this study was to identify the protein changes of serum exosomes in Parkinson disease (PD) patients with different disease progress types, and to identify potential biomarkers. The exosomes of PD patients with different severity and healthy control group were isolated from serum. The exosome proteins were analyzed by mass spectrometry with label-free quantitative proteomics. A total of 429 proteins were identified, of which 14 were significantly different in mild and severe PD patients. The expression levels of 7 proteins, including pigmented epithelium-derived factor, afamin, apolipoprotein D and J, were significantly increased in PD patients. The expression levels of 7 proteins, including complement C1q and protein Immunoglobulin Lambda Variable 1-33 (IGLV1-33)Cluster -33, were decreased in PD patients. These differentially expressed proteins were analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis, which confirmed that the interaction between prion diseases and ECM receptors was the most significant pathways of enrichment. The changes of proteins and pathways may be related to the pathophysiological mechanism of PD. Therefore, some of these proteins could be considered as potential biomarkers for early PD diagnosis.


Assuntos
Exossomos/genética , Doença de Parkinson/sangue , Doença de Parkinson/genética , Proteômica/métodos , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Progressão da Doença , Feminino , Ontologia Genética , Humanos , Masculino , Índice de Gravidade de Doença
2.
Toxicol Lett ; 316: 73-84, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31513886

RESUMO

In the liver microenvironment, interactions among diverse types of hepatic cells are involved in liver fibrosis. In fibrotic tissues, exosomes act as transporters in intercellular communication. Long non-coding RNAs (lncRNAs) are involved in the activation of hepatic stellate cells (HSCs), which are participants in liver fibrosis. However, the functions of exosomal lncRNAs in liver fibrosis induced by arsenite are undefined. The purposes of the present study were (a) to determine if lncRNAs secreted from human hepatic (L-02) cells exposed to arsenite are shuttled to hepatic stellate LX-2 cells and (b) to establish their effects on LX-2 cells. In mice, MALAT1 was overexpressed in the progression of liver fibrosis induced by arsenite as well as in L-02 cells exposed to arsenite. Co-cultures with arsenite-treated L-02 cells induced the activation of LX-2 cells and overexpression of MALAT1. Arsenite-treated L-02 cells transported MALAT1 into LX-2 cells. Downregulation of MALAT1, which reduced the MALAT1 levels in exosomes derived from arsenite-treated L-02 cells, inhibited the activation of LX-2 cells. Additionally, exosomal MALAT1 derived from arsenite-treated L-02 cells promoted the activation of LX-2 cells via microRNA-26b regulation of COL1A2. Furthermore, circulating exosomal MALAT1 was up-regulated in people exposed to arsenite. In sum, exosomes derived from arsenite-treated hepatic cells transferred MALAT1 to HSCs, which induced their activation. These findings support the concept that, during liver fibrosis induced by arsenite, exosomal lncRNAs are involved in cell-cell communication.


Assuntos
Arsenitos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Exossomos/metabolismo , Células Estreladas do Fígado/metabolismo , Cirrose Hepática Experimental/metabolismo , Fígado/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Compostos de Sódio , Animais , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Técnicas de Cocultura , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Exossomos/genética , Exossomos/ultraestrutura , Regulação da Expressão Gênica , Células Estreladas do Fígado/ultraestrutura , Humanos , Fígado/ultraestrutura , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/patologia , Masculino , Camundongos , MicroRNAs/genética , RNA Longo não Codificante/genética , Transdução de Sinais
3.
Toxicol Lett ; 316: 49-59, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520698

RESUMO

Epidemiological studies have established the correlations between PM2.5 and a wide variety of pulmonary diseases. However, their underlying pathogeneses have not been clearly elucidated yet. In the present study, the epithelial-mesenchymal transition (EMT) phenotype with enhanced proliferation and migration activity of human pulmonary epithelial cell line BEAS-2B was observed after exposure to low dose PM2.5 exposure (50 µg/ml) for 30 passages. Then, epithelial cells derived-exosomal micro-RNA (miRNA) and intracellular total RNA were extracted, and the differentially expressed exosomal miRNAs (DE-Exo-MiRs) as well as differentially expressed protein coding genes (DEGs) were identified by RNA sequencing (RNA-seq) and transcriptome analysis. We found that chronic PM2.5 exposure stimulated the release of pulmonary epithelium derived exosomes. 45 DE-Exo-MiRs including 32 novelly predicted miRNAs and 843 DEGs between PM2.5 exposed group and the normal control were detected. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses showed that DEGs were significantly enriched in extracellular matrix organization, focal adhesion and cancer related terms. Besides, the enrichment analyses on 7774 mRNA targets of 27 DE-Exo-MiRs predicted by MiRanda software also revealed the potential regulatory role of exosomal miRNAs in pathways in cancer, Wingless/Integrated (Wnt) signaling pathway, focal adhesion related genes and other multiple pathogenic pathways. Moreover, the interactive exosomal miRNA-mRNA pair networks were constructed using Cytoscape software. Our results provided a novel basis for a better understanding of the mechanisms of chronic PM2.5 exposure induced pulmonary disorders including pulmonary fibrosis and cancer, in which exosomal miRNAs (Exo-MiRs) potentially functions by dynamically regulating gene expressions.


Assuntos
Células Epiteliais/efeitos dos fármacos , Exossomos/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Pulmão/efeitos dos fármacos , MicroRNAs/genética , Material Particulado/toxicidade , RNA Mensageiro/genética , Transcriptoma/efeitos dos fármacos , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Biologia Computacional , Bases de Dados Genéticas , Células Epiteliais/metabolismo , Células Epiteliais/ultraestrutura , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Transição Epitelial-Mesenquimal/genética , Exossomos/genética , Exossomos/metabolismo , Exossomos/patologia , Redes Reguladoras de Genes , Humanos , Pulmão/metabolismo , Pulmão/ultraestrutura , MicroRNAs/metabolismo , Tamanho da Partícula , RNA Mensageiro/metabolismo , Medição de Risco , Fatores de Tempo , Testes de Toxicidade Crônica
4.
Oncol Rep ; 42(4): 1319-1328, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31364748

RESUMO

Oral squamous cell carcinoma (OSCC), with high potential for metastasis, is the most common malignant tumor of the head and neck. Cancer­associated fibroblasts (CAFs) are the main stromal cells in the microenvironment and aggravate tumor progression. However, whether CAFs are associated with the progression of OSCC remains unknown and the underlying mechanism remains unclear. In the present study, the role of CAFs in mediating OSCC cell migration and invasion was investigated, and the participation of exosomal miR­382­5p in this process was elucidated. In this study, according to the α­SMA staining with immunohistochemistry, 47 OSCC patients were divided into CAFs­rich and CAFs poor groups, and association of CAF density and clinicopathologic features of the OSCC patients were analyzed with Pearson χ2 test. Transwell assay was used for evaluating cell migration and invasion ability of OSCC cells after being co­cultured with NFs or CAFs, or after added exosomes. qPCR was used to detect the expression of miR­382­5p. Western blot analysis was used to measure the expression of migration and invasion­associated proteins. In the present study, the CAF density in tumor tissues was found to be relevant to OSCC lymph node metastasis and TNM stage. Furthermore, we revealed that miR­382­5p was overexpressed in CAFs compared with that in fibroblasts of adjacent normal tissue and miR­382­5p overexpression was responsible for OSCC cell migration and invasion. Finally, we demonstrated that CAF­derived exosomes transported miR­382­5p to OSCC cells. The present study confirmed a new mechanism of CAF­facilitated OSCC progression and may be beneficial for identifying new cancer therapeutic targets.


Assuntos
Fibroblastos Associados a Câncer/patologia , Exossomos/genética , MicroRNAs/biossíntese , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Actinas/biossíntese , Adulto , Idoso , Fibroblastos Associados a Câncer/metabolismo , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Exossomos/metabolismo , Exossomos/patologia , Feminino , Humanos , Imuno-Histoquímica , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Metástase Neoplásica , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo
5.
J Agric Food Chem ; 67(34): 9477-9491, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31429552

RESUMO

Lipopolysaccharide (LPS) is a bacterial endotoxin that induces intestine inflammation. Milk exosomes improve the intestine and immune system development of newborns. This study aims to establish the protective mechanisms of porcine milk exosomes on the attenuation of LPS-induced intestinal inflammation and apoptosis. In vivo, exosomes prevented LPS-induced intestine damage and inhibited (p < 0.05) LPS-induced inflammation. In vitro, exosomes inhibited (p < 0.05) LPS-induced intestinal epithelial cells apoptosis (23% ± 0.4% to 12% ± 0.2%). Porcine milk exosomes also decreased (p < 0.05) the LPS-induced TLR4/NF-κB signaling pathway activation. Furthermore, exosome miR-4334 and miR-219 reduced (p < 0.05) LPS-induced inflammation through the NF-κB pathway and miR-338 inhibited (p < 0.05) the LPS-induced apoptosis via the p53 pathway. Cotransfection with these three miRNAs more effectively prevented (p < 0.05) LPS-induced cell apoptosis than these miRNAs individual transfection. The apoptosis percentage in the group cotransfected with the three miRNAs (14% ± 0.4%) was lower (p < 0.05) than that in the NC miRNA group (28% ± 0.5%), and also lower than that in each individual miRNA group. In conclusion, porcine milk exosomes protect the intestine epithelial cells against LPS-induced injury by inhibiting cell inflammation and protecting against apoptosis through the action of exosome miRNAs. The presented results suggest that the physiological amounts of miRNAs-enriched exosomes addition to infant formula could be used as a novel preventative measure for necrotizing enterocolitis.


Assuntos
Apoptose , Células Epiteliais/citologia , Exossomos/metabolismo , MicroRNAs/metabolismo , Leite/metabolismo , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Células Epiteliais/metabolismo , Exossomos/genética , Mucosa Intestinal/citologia , Mucosa Intestinal/metabolismo , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , MicroRNAs/genética , NF-kappa B/genética , Transdução de Sinais , Suínos , Receptor 4 Toll-Like/genética , Proteína Supressora de Tumor p53/genética
6.
Int J Nanomedicine ; 14: 5637-5657, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31413567

RESUMO

Background: Preeclampsia is the leading cause of maternal and fetal mortality due to the inability to diagnose and treat the disorder early in pregnancy. This is attributed to the complex pathophysiology and unknown etiology of the disorder, which is modulated by several known and unknown factors. Exosomes have recently been implicated as possible mediators of the pathogenesis of preeclampsia, with, however, no evidence linking these nanovesicles to the pathophysiology of preeclampsia and its subtypes. Methods: To better understand the pathophysiological role of exosomes in preeclampsia, we have analyzed the exosomal microRNA in early and late onset preeclamptic women in comparison to their gestationally matched normotensive controls using Digital Direct Detection (NanoString Technologies). Results: For the first time, distinct exosomal microRNA signatures in early and late onset preeclampsia have been identified. Moreover, these signatures indicate that exosomes are involved in key pathological features associated with preeclampsia and differentiate between the subtypes. Conclusion: This study forms the basis for the diagnostic and functional validation of the identified signatures as biomarkers of preeclampsia and its subtypes.


Assuntos
Exossomos/genética , Perfilação da Expressão Gênica , MicroRNAs/metabolismo , Pré-Eclâmpsia/genética , Pré-Eclâmpsia/fisiopatologia , Adulto , Pressão Sanguínea , Feminino , Ontologia Genética , Humanos , Gravidez , Reprodutibilidade dos Testes
7.
Anticancer Res ; 39(8): 4055-4060, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366487

RESUMO

BACKGROUND/AIM: Tumor-derived exosomes play important roles in tumor metastases. In this report, we observed the fate of tumor-derived exosomes in pancreatic cancer metastatic nude-mouse models using color-coded imaging. MATERIALS AND METHODS: Mia-PaCa-2 human pancreatic cancer cells expressing red fluorescent protein (RFP) were transduced by exosome-specific pCT-CD63-green fluorescent protein (GFP) and injected in the spleen of nude mice. RESULTS: Four weeks after injection of these cells into the spleen, liver metastases developed and tumor-derived exosomes were observed within the metastatic cancer cells and in Kupffer cells. Furthermore, tumor-derived exosomes diffused to bone marrow and lung cells, especially macrophages, without any metastases present. CONCLUSION: In the present study, we visualized the distribution of cancer-derived exosomes for the first time at the cellular level, in a pancreatic-cancer metastatic model.


Assuntos
Linhagem da Célula/genética , Exossomos/genética , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Animais , Modelos Animais de Doenças , Proteínas de Fluorescência Verde/química , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Proteínas Luminescentes/química , Camundongos , Metástase Neoplásica , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cell Mol Life Sci ; 76(21): 4203-4219, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31300868

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, with a high mortality rate. Its dismal prognosis is attributed to late diagnosis, high risk of recurrence and drug resistance. To improve the survival of patients with HCC, new approaches are required for early diagnosis, real-time monitoring and effective treatment. Exosomes are small membranous vesicles released by most cells that contain biological molecules and play a great role in intercellular communication under physiological or pathological conditions. In cancer, exosomes from tumor cells or non-tumor cells can be taken up by neighboring or distant target cells, and the cargoes in exosomes are functional to modulate the behaviors of tumors or reshape tumor microenvironment (TME). As essential components, non-coding RNAs (ncRNAs) are selectively enriched in exosomes, and exosomal ncRNAs participate in regulating specific aspects of tumor development, including tumorigenesis, tumor metastasis, angiogenesis, immunomodulation and drug resistance. Besides, dysregulated exosomal ncRNAs have emerged as potential biomarkers, and exosomes can serve as natural vehicles to deliver tumor-suppressed ncRNAs for treatment. In this review, we briefly summarize the biology of exosomes, the functions of exosomal ncRNAs in HCC development and their potential clinical applications, including as biomarkers and therapeutic tools.


Assuntos
Carcinoma Hepatocelular/genética , Exossomos/genética , Neoplasias Hepáticas/genética , RNA Neoplásico/fisiologia , RNA não Traduzido/fisiologia , Animais , Biomarcadores Tumorais/fisiologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Sistemas de Liberação de Medicamentos , Exossomos/metabolismo , Regulação Neoplásica da Expressão Gênica , Terapia Genética/métodos , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Terapia de Alvo Molecular/métodos , RNA Neoplásico/metabolismo , RNA não Traduzido/metabolismo
9.
Cell Physiol Biochem ; 53(1): 19-35, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31162914

RESUMO

BACKGROUND/AIMS: Emerging evidence suggests that exosomal microRNAs (miRNAs) mediate hepatoma progression through the post-translational regulation of their targets. However, characteristically-expressed miRNAs and their functions in the tumor and tumor-associated angiogenesis remain poorly understood. METHODS: miRNA sequencing (HiSeq 2500 SE50) was performed to identify miRNA species that are involved in the hepatocellular carcinoma (HCC) pathogenesis. We identified miR-451a downregulation according to its expression and TCGA analysis. miR-451a was found to be mainly involved in cell viability, apoptosis, cell cycle and migration both in HCC and endothelial cell lines. LPIN1 was predicted to be a target of this miRNA based on TargetScan, GSEA analysis, and the Uniprot database. We performed real time PCR and dual luciferase assays to confirm these results. RESULTS: We identified that miR-451a is significantly downregulated in serum-derived exosomes from HCC patients, as compared to expression in those from normal individuals. We further confirmed that overexpression of miR-451a functions in HCC and endothelia cells in vitro and in vivo. Exosomal miR-451a, as a tumor suppressor, was found to induce apoptosis both in HCC cell lines and human umbilical vein endothelial cells (HUVECs). In addition, miR-451a suppressed HUVEC migration, tube formation, and vascular permeability. Importantly, we demonstrated that LPIN1 is a critical target of miR-451a, and promotes apoptosis in both HCC and endothelial cells. CONCLUSION: Our study provides the novel finding that exosomal miR-451a targets LPIN1 to inhibit hepatocellular tumorigenesis by regulating tumor cell apoptosis and angiogenesis. These results have clinical implications regarding the deregulation of miRNAs in HCC.


Assuntos
Carcinoma Hepatocelular/genética , Exossomos/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/genética , MicroRNAs/genética , Fosfatidato Fosfatase/genética , Apoptose , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Exossomos/patologia , Genes Supressores de Tumor , Células Endoteliais da Veia Umbilical Humana , Humanos , Neoplasias Hepáticas/patologia
10.
Gene ; 710: 258-264, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31176731

RESUMO

OBJECTIVE: Increasing evidence indicated that cancer-secreted exosomes played an important role in tumor metastasis. However, the function of exosomes in breast cancer pulmonary metastasis remains unknown. The aim of the study was to investigate the role of exosome-derived from breast cancer-secreted long non-coding RNAs (LncRNAs) on pre-metastatic niche formation in pulmonary metastasis. METHODS: Exosomes-derived from breast cancer were separated by ultracentrifugation. The high-throughput sequencing, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were used to detect and evaluate the differential expression of LncRNAs in lung fibroblasts with exosomes treated. And quantitative real-time polymerase chain reaction (qRT-PCR) was performed to verify candidate LncRNAs expression. RESULTS: We found that exosomes-derived from breast cancer induced lung fibroblasts proliferation and migration. In addition, a large number of LncRNAs expression abnormalities were involved in the breast cancer lung metastasis microenvironment. CONCLUSION: Our findings suggested that exosomal LncRNAs facilitated tumor pre-metastatic niche formation and represented a novel mechanistic insight into the molecular mechanism of cancer metastasis microenvironment.


Assuntos
Neoplasias da Mama/genética , Exossomos/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neoplasias Pulmonares/secundário , RNA Longo não Codificante/genética , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Neoplasias Pulmonares/genética , Análise de Sequência de RNA/métodos , Microambiente Tumoral
11.
Cancer Sci ; 110(8): 2396-2407, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31148360

RESUMO

The tumor microenvironment offers favorable conditions for tumor progression, and activated fibroblasts, known as cancer-associated fibroblasts, play a pivotal role. TP53-deficient cancer cells are known to induce strong fibroblast activation. We aimed to elucidate the oncogenic role of exosomes derived from TP53-deficient colon cancer cells in fibroblast proliferation and tumor growth. Cancer cell-derived exosomes (CDEs) were isolated from the conditioned media of cancer cells using a sequential ultracentrifugation method. The effects of exosomes on tumor growth were evaluated using human cell lines (TP53-WT colon cancer, HCT116; TP53-mutant colon cancer, HT29; and fibroblasts, CCD-18Co and WI-38) and an immune-deficient nude mouse xenograft model. HCT116 (HCT116sh p53 ) cells deficient in TP53 accelerated cocultured fibroblast proliferation compared to TP53-WT HCT116 (HCT116sh control ) cells in vitro. Exosomes from HCT116sh p53 cells suppressed TP53 expression of fibroblasts and promoted their proliferation. Xenografts of HCT116sh p53 cells grew significantly faster than those of HCT116sh control cells in the presence of co-injected fibroblasts, but this difference was diminished by CDE inhibition. Microarray analysis identified upregulation of several microRNAs (miR-1249-5p, miR-6737-5p, and miR-6819-5p) in TP53-deficient CDEs, which were functionally proven to suppress TP53 expression in fibroblasts. Exosomes derived from TP53-mutant HT29 cells also suppressed TP53 expression in fibroblasts and accelerated their growth. The proliferative effect of HT29 on cocultured fibroblasts was diminished by inhibition of these miRNAs in fibroblasts. Our results suggest that CDEs play a pivotal role in tumor progression by fibroblast modification. Cancer cell-derived exosomes might, therefore, represent a novel therapeutic target in colon cancer.


Assuntos
Neoplasias do Colo/genética , Exossomos/genética , MicroRNAs/genética , Proteína Supressora de Tumor p53/genética , Animais , Fibroblastos Associados a Câncer/patologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Neoplasias do Colo/patologia , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/genética , Células HCT116 , Células HT29 , Xenoenxertos/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transdução de Sinais/genética , Microambiente Tumoral/genética , Regulação para Cima/genética
12.
Biomed Res Int ; 2019: 1495130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31073519

RESUMO

Objective: With the development of exosomes studies increased around the whole world. Our present study was aimed to investigate the global status and trends in exosomes field. Methods: Publications related to exosomes studies from 1994 to 2017 were retrieved from the Web of Science database. The data source was studied and indexed by using bibliometric methodology. For visualized study, VOS viewer software was used to conduct bibliographic coupling analysis, coauthorship analysis, cocitation analysis, and cooccurrence analysis and to analyze the publication trend in exosomes research. Results: A total of 4960 publications were included. The relative research interests and number of publications were increasing per year globally. The USA made the highest contributions to the global research with the most citations, the highest H-index, and the most total link strength, while Sweden had the highest average citation per item. The journal PLOS ONE had the highest publication number. The Natl Canc Ctr was the most contributive institutions. Studies could be divided into three clusters: mechanism study, in vivo study, and in vitro study. Conclusions: The efforts should be put into mechanism studies, predicted to be the next hot spots in exosomes studies.


Assuntos
Endocitose/genética , Exossomos/genética , Revisão da Pesquisa por Pares , Bases de Dados Factuais , Exossomos/ultraestrutura , Vesículas Extracelulares/genética , Humanos , Publicações , Suécia
13.
Cancer Sci ; 110(7): 2119-2132, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31141251

RESUMO

Locally advanced and metastatic invasive bladder cancer (BC) has a poor prognosis, and no advanced therapies beyond cisplatin-based combination chemotherapy have been developed. Therefore, it is an urgent issue to elucidate the underlying mechanisms of tumor progression and metastasis of invasive BC for the development of new therapeutic strategies. Here, we clarified a novel role of exosomes containing ErbB2 and CRK in a formation of premetastatic niches and subsequent metastases. CRK adaptors were overexpressed in invasive UM-UC-3 BC cells. In an orthotopic xenograft model, metastases to lung, liver, and bone of UM-UC-3 cells were completely abolished by CRK elimination. Mass spectrometry analysis identified that ErbB2 was contained in UM-UC-3-derived exosomes in a CRK-dependent manner; the exosomes significantly increased proliferation and invasion properties of low-grade 5637 BC cells and HUVECs through FAK and PI3K/AKT signaling pathways. In athymic mice educated with UM-UC-3-derived exosomes, i.v. implanted UM-UC-3 cells were trapped with surrounding PKH67-labeled exosomes in lung and led to development of lung metastasis with disordered vascular proliferation. In contrast, exosomes derived from CRK-depleted BC cells failed to induce these malignant features. Taken together, we showed that CRK adaptors elevated the expression of ErbB2/3 in BC cells, and these tyrosine kinase/adaptor units were transferred from host BC cells to metastatic recipient cells by exosomes, leading to vascular leakiness and proliferation and contributing to the formation of distant metastasis. Thus, CRK intervention with ErbB2/3 blockade might be a potent therapeutic strategy for patients with ErbB2 overexpressing advanced and metastatic BC.


Assuntos
Exossomos/patologia , Proteínas Proto-Oncogênicas c-crk/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias da Bexiga Urinária/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Transição Epitelial-Mesenquimal , Exossomos/genética , Exossomos/metabolismo , Humanos , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Proteínas Proto-Oncogênicas c-crk/genética , Receptor ErbB-2/genética , Neoplasias da Bexiga Urinária/irrigação sanguínea , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/metabolismo
14.
Int J Biol Macromol ; 132: 470-477, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30936013

RESUMO

Circulating exosomal microRNAs (exomiR) have been demonstrated to be novel diagnostic biomarkers for various cancers. In this study, we found that circulating exomiR-1229 levels were significantly increased in the serum exosomes of patients with colorectal cancer (CRC) and significantly associated with tumor size, lymphatic metastasis, TNM stage and poor survival. Treatment with siRNA-Drosha, siRNA-ALIX and GW4869 repressed the expression of exomiR-1229 secreted from CRC cells. Both CRC-derived exosomes and exomiR-1229 mimic promoted the tubulogenesis of HUVECs, but transfection with exomiR-1229 inhibitor anta-miR-1229 significantly suppressed tube formation. Subsequently, HIPK2 was identified as a target of exomiR-1229 and responsible for the effect of exomiR-1229 on angiogenesis of HUVECs. ExomiR-1229 inhibited the protein expression of HIPK2, thereby activating VEGF pathway. Finally, anta-miR-1229 effectively inhibited tumor growth and angiogenesis in the nude mouse xenograft model. These results highlighted a novel mechanism of CRC angiogenesis and the biological roles of exomiR-1229.


Assuntos
Proteínas de Transporte/genética , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/genética , Exossomos/genética , MicroRNAs/genética , Neovascularização Patológica/genética , Proteínas Serina-Treonina Quinases/genética , Adulto , Animais , Transformação Celular Neoplásica , Neoplasias Colorretais/patologia , Feminino , Células HCT116 , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade
15.
Cancer Genomics Proteomics ; 16(3): 163-173, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31018947

RESUMO

BACKGROUND/AIM: We examined the gene expression changes of breast cancer cells spontaneously undergoing epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET) and the role of exosomes in these transitions. MATERIALS AND METHODS: Highly invasive mesenchymal-like breast cancer cells, MDA-MB-231 (basal cells), EMT and MET variants, were characterized by microarray gene expression profiling, immunocytochemistry and chemo-sensitivity. RESULTS: Spontaneously disseminated cells were anoikis resistant, exhibited a dissociative, EMT-like phenotype and underwent MET when reseeded in cell-free plates. MET was inhibited by exosomes secreted by basal cells. Chemo-sensitivity to doxorubicin, vincristine and paclitaxel decreased in the order EMT

Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal , Exossomos/patologia , Regulação Neoplásica da Expressão Gênica , Transcriptoma , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Proliferação de Células , Exossomos/efeitos dos fármacos , Exossomos/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Células Tumorais Cultivadas
16.
J Exp Clin Cancer Res ; 38(1): 166, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992025

RESUMO

BACKGROUND: Acquired drug resistance is a constraining factor in clinical treatment of glioblastoma (GBM). However, the mechanisms of chemoresponsive tumors acquire therapeutic resistance remain poorly understood. Here, we aim to investigate whether temozolomide (TMZ) resistance of chemoresponsive GBM was enhanced by long non-coding RNA SBF2 antisense RNA 1 (lncRNA SBF2-AS1) enriched exosomes. METHOD: LncSBF2-AS1 level in TMZ-resistance or TMZ-sensitive GBM tissues and cells were analyzed by qRT-PCR and FISH assays. A series of in vitro assay and xenograft tumor models were performed to observe the effect of lncSBF2-AS1 on TMZ-resistance in GBM. CHIP assay were used to investigate the correlation of SBF2-AS1 and transcription factor zinc finger E-box binding homeobox 1 (ZEB1). Dual-luciferase reporter, RNA immunoprecipitation (RIP), immunofluorescence and western blotting were performed to verify the relation between lncSBF2-AS1, miR-151a-3p and XRCC4. Comet assay and immunoblotting were performed to expound the effect of lncSBF2-AS1 on DNA double-stand break (DSB) repair. A series of in vitro assay and intracranial xenografts tumor model were used to determined the function of exosomal lncSBF2-AS1. RESULT: It was found that SBF2-AS1 was upregulated in TMZ-resistant GBM cells and tissues, and overexpression of SBF2-AS1 led to the promotion of TMZ resistance, whereas its inhibition sensitized resistant GBM cells to TMZ. Transcription factor ZEB1 was found to directly bind to the SBF2-AS1 promoter region to regulate SBF2-AS1 level and affected TMZ resistance in GBM cells. SBF2-AS1 functions as a ceRNA for miR-151a-3p, leading to the disinhibition of its endogenous target, X-ray repair cross complementing 4 (XRCC4), which enhances DSB repair in GBM cells. Exosomes selected from temozolomide-resistant GBM cells had high levels of SBF2-AS1 and spread TMZ resistance to chemoresponsive GBM cells. Clinically, high levels of lncSBF2-AS1 in serum exosomes were associated with poor response to TMZ treatment in GBM patients. CONCLUSION: We can conclude that GBM cells remodel the tumor microenvironment to promote tumor chemotherapy-resistance by secreting the oncogenic lncSBF2-AS1-enriched exosomes. Thus, exosomal lncSBF2-AS1 in human serum may serve as a possible diagnostic marker for therapy-refractory GBM.


Assuntos
Proteínas de Ligação a DNA/genética , Glioblastoma/tratamento farmacológico , MicroRNAs/genética , RNA Longo não Codificante/genética , Animais , Biomarcadores Tumorais/sangue , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Exossomos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/sangue , Glioblastoma/genética , Glioblastoma/patologia , Humanos , Camundongos , Temozolomida/administração & dosagem , Temozolomida/efeitos adversos , Ensaios Antitumorais Modelo de Xenoenxerto , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
17.
Mol Cancer ; 18(1): 74, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940133

RESUMO

tRNA-derived small RNA (tsRNA) is a novel regulatory small non-coding RNA and participates in diverse physiological and pathological processes. However, the presence of tsRNAs in exosome and their diagnostic potential remain unclear. In this study, we took advantage of small RNA-seq technology to profile exosomal tsRNAs from cell culture medium and plasma, and found ubiquitous presence of tsRNAs in exosome. To explore the potential value of tsRNA for cancer diagnosis, we compared exosomal tsRNA levels between liver cancer patients and healthy donors, revealing that tsRNAs were dramatically increased in plasma exosomes of liver cancer patients. Importantly, patients with liver cancer exhibited significantly higher levels of four tsRNAs (tRNA-ValTAC-3, tRNA-GlyTCC-5, tRNA-ValAAC-5 and tRNA-GluCTC-5) in plasma exosome, demonstrating that plasma exosomal tsRNA could serve as a novel diagnostic biomarker. Taken together, our results not only expand non-coding RNA species in exosome, but also highlight the potential of tsRNAs as a promising biomarker for cancer diagnosis.


Assuntos
Exossomos/genética , Neoplasias/diagnóstico , RNA de Transferência/genética , RNA não Traduzido/genética , Biomarcadores Tumorais/genética , Técnicas de Cultura de Células , Detecção Precoce de Câncer , Humanos , Neoplasias/genética , Análise de Sequência de RNA , Células Tumorais Cultivadas
18.
Mol Cancer ; 18(1): 78, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30943982

RESUMO

BACKGROUND: Emerging evidence indicates that tumor cells release a large amount of exosomes loaded with cargos during tumorigenesis. Exosome secretion is a multi-step process regulated by certain related molecules. Long non-coding RNAs (lncRNAs) play an important role in hepatocellular carcinoma (HCC) progression. However, the role of lncRNA HOTAIR in regulating exosome secretion in HCC cells remains unclear. METHODS: We analyzed the relationship between HOTAIR expression and exosome secretion-related genes using gene set enrichment analysis (GSEA). Nanoparticle tracking analysis was performed to validate the effect of HOTAIR on exosome secretion. The transport of multivesicular bodies (MVBs) after overexpression of HOTAIR was detected by transmission electron microscopy and confocal microscopy analysis of cluster determinant 63 (CD63) with synaptosome associated protein 23 (SNAP23). The mechanism of HOTAIR's regulation of Ras-related protein Rab-35 (RAB35), vesicle associated membrane protein 3 (VAMP3), and SNAP23 was assessed using confocal co-localization analysis, phosphorylation assays, and rescue experiments. RESULTS: We found an enrichment of exosome secretion-related genes in the HOTAIR high expression group. HOTAIR promoted the release of exosomes by inducing MVB transport to the plasma membrane. HOTAIR regulated RAB35 expression and localization, which controlled the docking process. Moreover, HOTAIR facilitated the final step of fusion by influencing VAMP3 and SNAP23 colocalization. In addition, we validated that HOTAIR induced the phosphorylation of SNAP23 via mammalian target of rapamycin (mTOR) signaling. CONCLUSION: Our study demonstrated a novel function of lncRNA HOTAIR in promoting exosome secretion from HCC cells and provided a new understanding of lncRNAs in tumor cell biology.


Assuntos
Carcinoma Hepatocelular/genética , Exossomos/metabolismo , Neoplasias Hepáticas/genética , Proteínas Qb-SNARE/metabolismo , Proteínas Qc-SNARE/metabolismo , RNA Longo não Codificante/genética , Proteínas rab de Ligação ao GTP/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Exossomos/genética , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/metabolismo , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Fosforilação , Transporte Proteico , Proteínas Qb-SNARE/genética , Proteínas Qc-SNARE/genética , Transdução de Sinais , Proteínas rab de Ligação ao GTP/genética
19.
Mol Cancer ; 18(1): 86, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30975145

RESUMO

BACKGROUND: Clear cell renal cell carcinoma (CCRCC) is characterized by a highly metastatic potential. The stromal communication between stem cells and cancer cells critically influences metastatic dissemination of cancer cells. METHODS: The effect of exosomes isolated from cancer stem cells (CSCs) of CCRCC patients on the progress of epithelial-mesenchymal transition (EMT) and lung metastasis of CCRCC cells were examined. RESULTS: CSCs exosomes promoted proliferation of CCRCC cells and accelerated the progress of EMT. Bioactive miR-19b-3p transmitted to cancer cells by CSC exosomes induced EMT via repressing the expression of PTEN. CSCs exosomes derived from CCRCC patients with lung metastasis produced the strongest promoting effect on EMT. Notably, CD103+ CSC exosomes were enriched in tumor cells and in lung as well, highlighting the organotropism conferred by CD103. In addition, CD103+ exosomes were increased in blood samples from CCRCC patients with lung metastasis. CONCLUSIONS: CSC exosomes transported miR-19b-3p into CCRCC cells and initiated EMT promoting metastasis. CD103+ acted to guide CSC exosomes to target cancer cells and organs, conferring the higher metastatic capacity of CCRCC to lungs, suggesting CD103+ exosomes as a potential metastatic diagnostic biomarker. ᅟ.


Assuntos
Antígenos CD/genética , Carcinoma de Células Renais/genética , Exossomos/metabolismo , Cadeias alfa de Integrinas/genética , Neoplasias Renais/genética , Neoplasias Pulmonares/genética , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Animais , Antígenos CD/metabolismo , Transporte Biológico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/metabolismo , Carcinoma de Células Renais/secundário , Comunicação Celular , Linhagem Celular Tumoral , Proliferação de Células , Transição Epitelial-Mesenquimal/genética , Exossomos/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Cadeias alfa de Integrinas/metabolismo , Neoplasias Renais/metabolismo , Neoplasias Renais/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Metástase Linfática , Camundongos Nus , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , PTEN Fosfo-Hidrolase/metabolismo , Transdução de Sinais , Células Estromais/metabolismo , Células Estromais/patologia , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Genet Test Mol Biomarkers ; 23(4): 235-240, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30986097

RESUMO

AIMS: Evaluation of nucleic acids in plasma exosomes is a noninvasive method that can be used to detect different types of cancer. The aim of this study was to determine the value of exosomal long noncoding RNAs (lncRNAs) in detecting lung squamous cell carcinoma (LSCC). MATERIALS AND METHODS: A total of 75 LSCC patients and 79 negative control subjects were enrolled in the study. Twenty differentially expressed lncRNAs were evaluated as potential candidates. Exosomes were isolated by ultracentrifugation, and lncRNA levels in exosomes were determined using real-time polymerase chain reaction. Receiver Operating Characteristic (ROC) curves were used to determine specificity and sensitivity. RESULTS: Exosomal SOX2-OT was significantly upregulated in LSCC patients and showed the strongest power in detecting LSCC. The area under the ROC curve was 0.815, and the sensitivity and specificity were 76% and 73.17%, respectively. Moreover, exosomal SOX2-OT levels were significantly correlated with tumor size, TNM stage, and lymph node metastasis. Exosomal SOX2-OT levels were significantly decreased in the postoperative plasma of LSCC patients. CONCLUSION: SOX2-OT may serve as a promising noninvasive plasma-based tumor biomarker for LSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Complexo Multienzimático de Ribonucleases do Exossomo/genética , Fatores de Transcrição SOXB1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Complexo Multienzimático de Ribonucleases do Exossomo/sangue , Exossomos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Homologia de Genes/genética , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Metástase Linfática , Masculino , Pessoa de Meia-Idade , RNA Longo não Codificante/análise , RNA Longo não Codificante/genética , Curva ROC , Sensibilidade e Especificidade
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