60 results on '"Hui Qian"'
Search Results
2. Exosomal circ50547 as a potential marker and promotor of gastric cancer progression via miR-217/HNF1B axis
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Xueyan Zang, Rongrong Wang, Ziyi Wang, Shuangyang Qiu, Fan Zhang, Le Zhou, Ye Shen, Hui Qian, Wenrong Xu, and Jiajia Jiang
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Exosomes ,CircRNAs ,Gastric cancer ,miRNA ,Stem,Resistance ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background: Exosomes, one of small extracellular vesicles, play a vital role in cell to cell communication and contribute to the advancement of tumors through their cargo molecules. Exosomal circRNAs have emerged as significant players in various types of tumors. Thus, this study aimed to investigate how exosomal circRNAs are involved in the diagnosis and progression of gastric cancer (GC). Methods: Serum exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis and Western blot. CCK-8, colony formation and transwell assays were conducted to study the function of hsa_circ_0050547 (named as circ50547). qRT-PCR was used to quantify the expression of circ50547 in GC tissues and serum exosomes. Fluorescence in situ hybridization was applied to detect the cellular distribution of circ50547. Stemness and drug-resistance were detected by sphere formation, WB, flow cytometry and half-maximal inhibitory concentration analyses. Bioinformatic analyses, luciferase experiments, qRT-PCR and WB were used to investigate molecular mechanisms. Results: We discovered for the first time a new type of GC-derived exosomal circRNA, circ50547. We found that circ50547 is highly expressed in both GC tissues and serum exosomes. Interestingly, we observed that the diagnostic value of exosomal circ50547 is superior to that of serum circ50547. Circ50547 overexpression enhanced the proliferation, migration, invasion, stemness and drug resistance of GC cells, while knockdown of circ50547 showed the opposite effect. Mechanistically, circ50547 acted as a sponge for miR-217 to regulate the expression of HNF1B, which promoted gastric cancer progression. Conclusion: Exosomal circ50547 may be a promising marker for the diagnosis and prognosis prediction of GC. These findings suggest that it plays an oncogenic role through miR-217/HNF1B signaling pathway in GC.
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- 2024
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3. Exosomal hsa_circ_000200 as a potential biomarker and metastasis enhancer of gastric cancer via miR-4659a/b-3p/HBEGF axis
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Xiao-juan Huang, Yan Wang, Hui-ting Wang, Zhao-feng Liang, Cheng Ji, Xiao-xi Li, Lei-lei Zhang, Run-bi Ji, Wen-rong Xu, Jian-hua Jin, and Hui Qian
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Exosomes ,hsa_circ_000200 ,Gastric cancer ,Liquid biopsy marker ,miR-4659a/b-3p ,HBEGF ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract Background Exosome, a component of liquid biopsy, loaded protein, DNA, RNA and lipid gradually emerges as biomarker in tumors. However, exosomal circRNAs as biomarker and function mechanism in gastric cancer (GC) are not well understood. Methods Differentially expressed circRNAs in GC and healthy people were screened by database. The identification of hsa_circ_000200 was verified by RNase R and sequencing, and the expression of hsa_circ_000200 was evaluated using qRT-PCR. The biological function of hsa_circ_000200 in GC was verified in vitro. Western blot, RIP, RNA fluorescence in situ hybridization, and double luciferase assay were utilized to explore the potential mechanism of hsa_circ_000200. Results Hsa_circ_000200 up-regulated in GC tissue, serum and serum exosomes. Hsa_circ_000200 in serum exosomes showed better diagnostic ability than that of tissues and serum. Combined with clinicopathological parameters, its level was related to invasion depth, TNM staging, and distal metastasis. Functionally, knockdown of hsa_circ_000200 inhibited GC cells proliferation, migration and invasion in vitro, while its overexpression played the opposite role. Importantly, exosomes with up-regulated hsa_circ_000200 promoted the proliferation and migration of co-cultured GC cells. Mechanistically, hsa_circ_000200 acted as a “ceRNA” for miR-4659a/b-3p to increase HBEGF and TGF-β/Smad expression, then promoted the development of GC. Conclusions Our findings suggest that hsa_circ_000200 promotes the progression of GC through hsa_circ_000200/miR-4659a/b-3p/HBEGF axis and affecting the expression of TGF-β/Smad. Serum exosomal hsa_circ_000200 may serve as a potential biomarker for GC.
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- 2023
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4. Cigarette Smoke-Induced Gastric Cancer Cell Exosomes Affected the Fate of Surrounding Normal Cells via the Circ0000670/Wnt/β-Catenin Axis
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Zhaofeng Liang, Shikun Fang, Yue Zhang, Xinyi Zhang, Yumeng Xu, Hui Qian, and Hao Geng
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gastric cancer ,cigarette smoke ,circRNA ,exosomes ,Wnt/β-catenin ,Chemical technology ,TP1-1185 - Abstract
Cigarette smoke is a major risk factor for gastric cancer. Exosomes are an important part of intercellular and intra-organ communication systems and can carry circRNA and other components to play a regulatory role in the occurrence and development of gastric cancer. However, it is unclear whether cigarette smoke can affect exosomes and exosomal circRNA to promote the development of gastric cancer. Exosomes secreted by cancer cells promote cancer development by affecting surrounding normal cells. Herein, we aimed to clarify whether the exosomes secreted by cigarette smoke-induced gastric cancer cells can promote the development of gastric cancer by affecting the surrounding gastric mucosal epithelial cells (GES-1). In the present study, we treated gastric cancer cells with cigarette smoke extract for 4 days and demonstrated that cigarette smoke promotes the stemness and EMT of gastric cancer cells and cigarette smoke-induced exosomes promote stemness gene expression, EMT processes and the proliferation of GES-1 cells. We further found that circ0000670 was up-regulated in tissues of gastric cancer patients with smoking history, cigarette smoke-induced gastric cancer cells and their exosomes. Functional assays showed that circ0000670 knockdown inhibited the promoting effects of cigarette smoke-induced exosomes on the stemness and EMT characteristic of GES-1 cells, whereas its overexpression had the opposite effect. In addition, exosomal circ0000670 was found to promote the development of gastric cancer by regulating the Wnt/β-catenin pathway. Our findings indicated that exosomal circ0000670 promotes cigarette smoke-induced gastric cancer development, which might provide a new basis for the treatment of cigarette smoke-related gastric cancer.
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- 2023
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5. Exosomal LncRNAs in Gastrointestinal Cancer: Biological Functions and Emerging Clinical Applications
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Yuntong Sun, Fengtian Sun, Jianhua Jin, Wenrong Xu, and Hui Qian
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exosomes ,lncRNAs ,gastrointestinal cancer ,biomarker ,therapeutic target ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Due to the lack of specific and effective biomarkers and therapeutic targets, the early diagnosis and treatment of gastrointestinal cancer remain unsatisfactory. As a type of nanosized vesicles derived from living cells, exosomes mediate cell-to-cell communication by transporting bioactive molecules, thus participating in the regulation of many pathophysiological processes. Recent evidence has revealed that several long non-coding RNAs (lncRNAs) are enriched in exosomes. Exosomes-mediated lncRNAs delivery is critically involved in various aspects of gastrointestinal cancer progression, such as tumor proliferation, metastasis, angiogenesis, stemness, immune microenvironment, and drug resistance. Exosomal lncRNAs represent promising candidates to act as the diagnosis biomarkers and anti-tumor targets. This review introduces the major characteristics of exosomes and lncRNAs and describes the biological functions of exosomal lncRNAs in gastrointestinal cancer development. The preclinical studies on using exosomal lncRNAs to monitor and treat gastrointestinal cancer are also discussed, and the opportunities and challenges for translating them into clinical practice are evaluated.
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- 2023
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6. Implications of Crosstalk between Exosome-Mediated Ferroptosis and Diseases for Pathogenesis and Treatment
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Zixuan Zhou, Benshuai You, Cheng Ji, Leilei Zhang, Feng Wu, and Hui Qian
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exosomes ,ferroptosis ,ferroptosis therapy ,Cytology ,QH573-671 - Abstract
Ferroptosis is a type of iron-dependent cell death caused by ferrous iron overload, reactive oxygen species generation through the Fenton reaction, and lipid peroxidation, leading to antioxidative system dysfunction and, ultimately, cell membrane damage. The functional role of ferroptosis in human physiology and pathology is considered a cause or consequence of diseases. Circulating exosomes mediate intercellular communication and organ crosstalk. They not only transport functional proteins and nucleic acids derived from parental cells but also serve as vehicles for the targeted delivery of exogenous cargo. Exosomes regulate ferroptosis by delivering the biological material to the recipient cell, affecting ferroptosis-related proteins, or transporting ferritin-bound iron out of the cell. This review discusses pathogenesis mediated by endogenous exosomes and the therapeutic potential of exogenous exosomes for ferroptosis-related diseases. In addition, this review explores the role of exosome-mediated ferroptosis in ferroptosis-related diseases with an emphasis on strategies for engineering exosomes for ferroptosis therapy.
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- 2023
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7. Exosomes: Emerging Cell-Free Based Therapeutics in Dermatologic Diseases
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Hui Shi, Min Wang, Yaoxiang Sun, Dakai Yang, Wenrong Xu, and Hui Qian
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exosomes ,cell-free therapy ,cell communication ,bioengineering ,dermatologic diseases ,Biology (General) ,QH301-705.5 - Abstract
Exosomes are lipid bilayer vesicles released by multiple cell types. These bioactive vesicles are gradually becoming a leading star in intercellular communication involving in various pathological and physiological process. Exosomes convey specific and bioactive transporting cargos, including lipids, nucleic acids and proteins which can be reflective of their parent cells, rendering them attractive in cell-free therapeutics. Numerous findings have confirmed the crucial role of exosomes in restraining scars, burning, senescence and wound recovery. Moreover, the biology research of exosomes in cutting-edge studies are emerging, allowing for the development of particular guidelines and quality control methodology, which favor their possible application in the future. In this review, we discussed therapeutic potential of exosomes in different relevant mode of dermatologic diseases, as well as the various molecular mechanisms. Furthermore, given the advantages of favorable biocompatibility and transporting capacity, the bioengineering modification of exosomes is also involved.
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- 2021
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8. Exosomes in gastric cancer: roles, mechanisms, and applications
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Min Fu, Jianmei Gu, Pengcheng Jiang, Hui Qian, Wenrong Xu, and Xu Zhang
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Exosomes ,Gastric cancer ,Progression ,Biomarker ,Target ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Exosomes are nanosized extracellular vesicles that can be released by almost all types of cells. Initially considered as the garbage bins acting to discard unwanted products of cells, exosomes are now recognized as an important way for cellular communication by transmitting bioactive molecules including proteins, DNA, mRNAs, and non-coding RNAs. The recent studies have shown that exosomes are critically involved in human health and diseases including cancer. Exosomes have been suggested to participate in the promotion of tumorigenesis, tumor growth and metastasis, tumor angiogenesis, tumor immune escape, and tumor therapy resistance. Increasing evidence indicate that exosomes play important roles in gastric cancer development and progression. In this review, we summarized the current understanding of exosomes in gastric cancer with an emphasis on the biological roles of exosomes in gastric cancer and their potential as biomarkers for gastric cancer diagnosis as well as potential targets for gastric cancer therapy.
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- 2019
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9. Exosomal TRIM3 is a novel marker and therapy target for gastric cancer
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Hailong Fu, Huan Yang, Xu Zhang, Bo Wang, Jiahui Mao, Xia Li, Mei Wang, Bin Zhang, Zixuan Sun, Hui Qian, and Wenrong Xu
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Gastric cancer ,Exosomes ,TRIM3 ,Progression ,Diagnosis ,Therapy ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Exosomes are critically involved in cancer development and progression. The exosomal contents have been suggested as ideal cancer biomarkers. In this study, we investigated the expression of exosomal proteins in the serum of gastric cancer patients and their roles in gastric cancer. Methods The proteomic profile of exosomes from the serum of gastric cancer patients was detected by using LC-MS/MS. The expression of TRIM3 in exosomes from the serum of gastric cancer patients and healthy controls was assessed by ELISA and western blot. Immunohistochemistry was used to detect TRIM3 expression in gastric cancer tissues and their matching adjacent tissues. The growth and migration abilities of gastric cancer cells with TRIM3 overexpression or knockdown in vitro were evaluated by colony formation assay and transwell migration assay. The effects of TRIM3 overexpression or knockdown on gastric cancer growth and metastasis in vivo were investigated by using subcutaneous xenograft tumor and peritoneal metastasis mouse model. The effects of TRIM3-overexpressing exosomes on gastric cancer growth and metastasis in vitro and in vivo were also evaluated. Results We found that the expression levels of TRIM3 mRNA and protein were decreased in gastric cancer tissues compared to the matched control tissues. In addition, the levels of TRIM3 protein in the serum exosomes of gastric cancer patients were lower than that in healthy controls. We demonstrated that TRIM3 overexpression reduced while TRIM3 knockdown promoted the growth and metastasis of gastric cancer in vitro and in vivo through the regulation of stem cell factors and EMT regulators. Moreover, exosomes-mediated delivery of TRIM3 protein could suppress gastric cancer growth and metastasis in vitro and in vivo. Conclusions Taken together, our findings suggest that exosomal TRIM3 may serve as a biomarker for gastric cancer diagnosis and the delivery of TRIM3 by exosomes may provide a new avenue for gastric cancer therapy.
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- 2018
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10. Exosomal circRNAs: Novel biomarkers and therapeutic targets for gastrointestinal tumors
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Dongli Wang, Rong Li, Jiajia Jiang, Hui Qian, and Wenrong Xu
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Pharmacology ,Biomarkers, Tumor ,Tumor Microenvironment ,Humans ,General Medicine ,RNA, Circular ,Exosomes ,Biomarkers ,Gastrointestinal Neoplasms - Abstract
Despite the high prevalence of gastrointestinal tumors, early diagnosis and treatment of these tumors is limited by the lack of effective and specific biomarkers and therapeutic targets. Exosomes carry active molecules to mediate cell-to-cell communication, especially in the tumor microenvironment, and are promising biomarkers and therapeutic targets for cancer. Circular RNAs (circRNAs) are stably enriched in exosomes and show a unique circular structure, high stability, conservation, and tissue specificity. Exosomal circRNAs play important roles in regulating cell proliferation, metastasis, angiogenesis, metabolism, and the immune microenvironment of gastrointestinal tumors and exhibit great potential as tumor biomarkers and anti-tumor targets or tools. This review briefly introduces the characteristics and functions of circRNAs and exosomes, and systematically describes the biological roles and mechanisms of exosomal circRNAs in gastrointestinal tumors. This article also summarizes the detection methodology of exosomal circRNAs and discusses their clinical significance as biomarkers and targets for gastrointestinal tumors.
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- 2022
11. Gastric cancer stem cell-derived exosomes promoted tobacco smoke-triggered development of gastric cancer by inducing the expression of circ670
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Zhao feng Liang, Yue Zhang, Wenhao Guo, Bei Chen, Shikun Fang, and Hui Qian
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Cancer Research ,Oncology ,Stomach Neoplasms ,Tobacco ,Neoplastic Stem Cells ,Humans ,Tobacco Smoke Pollution ,Hematology ,General Medicine ,RNA, Circular ,Exosomes - Abstract
As one of the most common malignant cancers in the world, gastric cancer is caused by mang factors among which tobacco smoke is an important risk factor. Gastric cancer stem cells (GCSCs) and the derived exosomes play a key role in the occurrence and development of gastric cancer, and exosomal circRNA is considered as a new regulatory factor in the development of gastric cancer. However, it is unclear whether tobacco smoke can affect exosomes and their transport circRNAs to promote the development of gastric cancer. Herein, we provided a new insight into tobacco smoke promoting the progression of gastric cancer. In the present study, we demonstrated that tobacco smoke-induced exosomes promoted the spheroidizing ability, stemness genes expression, and epithelial-mesenchymal transition (EMT) process of GCSCs. We further found that hsa-circRNA-000670 (circ670) was up-regulated in tissues of gastric cancer patients with smoking history, tobacco smoke-induced GCSCs, and their exosomes. Functional assays have shown that circ670 knockdown inhibited the stemness and EMT process of GCSCs, whereas circ670 overexpression appeared to have an opposite effect. Our findings indicated that exosomal circ670 promotes the development of tobacco smoke-induced gastric cancer, which may provide insight into the mechanism of tobacco smoke promoting the progression of gastric cancer.
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- 2022
12. Neutrophil membrane engineered HucMSC sEVs alleviate cisplatin-induced AKI by enhancing cellular uptake and targeting
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Peipei, Wu, Yuting, Tang, Can, Jin, Min, Wang, Linli, Li, Zhong, Liu, Hui, Shi, Zixuan, Sun, Xiaomei, Hou, Wenya, Chen, Wenrong, Xu, and Hui, Qian
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Neutrophils ,Biomedical Engineering ,Humans ,Pharmaceutical Science ,Molecular Medicine ,Medicine (miscellaneous) ,Bioengineering ,Acute Kidney Injury ,Cisplatin ,Exosomes ,Applied Microbiology and Biotechnology ,Umbilical Cord - Abstract
Human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (hucMSC-sEVs) have been demonstrated as a therapeutic agent to prevent and treat cisplatin-induced acute kidney injury (AKI). However, hucMSC-sEVs still face many problems and challenges in the repair and treatment of tissue injury, including short circulation time, insufficient targeting, and low therapeutic efficacy. Therefore, we constructed engineered hybrid vesicles fused with nanovesicles derived from human neutrophil membranes and hucMSC-sEVs, named neutrophil membrane engineered hucMSC-sEVs (NEX). NEX significantly enhanced the targeting of hucMSC-sEVs to injured kidney tissues, improved the impaired renal function via reducing pro-inflammatory cytokines expression, promoted the proliferation of renal tissue cells, and inhibited renal cell apoptosis in vivo. In addition, NEX enhanced hucMSC-sEVs uptake by NRK52E cells, but inhibited its uptake by RAW264.7 cells. Moreover, administration of NEX reduced cellular oxidative stress and promoted proliferation of NRK52E cells treated with cisplatin in vitro. In summary, our findings indicate that this design of a universal approach enhances the targeting and therapeutic efficacy of hucMSC-sEVs in kidney tissue regeneration, and provides new evidence promoting its clinical application.
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- 2022
13. Small extracellular vesicles isolation and separation: Current techniques, pending questions and clinical applications
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Yuanwang Jia, Li Yu, Tieliang Ma, Wenrong Xu, Hui Qian, Yaoxiang Sun, and Hui Shi
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Extracellular Vesicles ,Drug Delivery Systems ,Medicine (miscellaneous) ,Proteins ,Cell Communication ,Exosomes ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) - Abstract
Extracellular vesicles, especially small extracellular vesicles (sEVs) are now accepted as important messengers in cell-to-cell communication and as a promising drug delivery platform. They are involved in nearly all physiological and pathological processes and are involved in disease diagnosis and therapy. However, their heterogeneity of physicochemical properties and functions is not fully understood, which hinders further clinical applications. To obtain highly bioactive sEVs with both high yield and purity, will certainly facilitate their future study and application. This review informs up-to-date research on frequently-used and cutting-edge technologies of sEVs isolation and makes a deep comparison and analysis of different methods, including their advantages, limitations and applications. Pending questions about the inherent property of these small vesicles as well as isolation strategies are discussed. Additionally, an overview of their applications in disease diagnosis and treatment, including some of the on-going clinical trials, are also reviewed.
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- 2022
14. HucMSC-derived exosomes delivered BECN1 induces ferroptosis of hepatic stellate cells via regulating the xCT/GPX4 axis
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Youwen Tan, Yan Huang, Rong Mei, Fei Mao, Dakai Yang, Jinwen Liu, Wenrong Xu, Hui Qian, and Yongmin Yan
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Liver Cirrhosis ,Cancer Research ,Immunology ,Mesenchymal Stem Cells ,Cell Biology ,Exosomes ,Phospholipid Hydroperoxide Glutathione Peroxidase ,Mice ,Cellular and Molecular Neuroscience ,Hepatic Stellate Cells ,Animals ,Ferroptosis ,Humans ,Beclin-1 - Abstract
Activated hepatic stellate cells (HSCs) are significant in liver fibrosis. Our past investigations have shown that human umbilical cord mesenchymal stem cells (hucMSCs) and their secreted exosomes (MSC-ex) could alleviate liver fibrosis via restraining HSCs activation. However, the mechanisms underlying the efficacy were not clear. Ferroptosis is a regulatory cell death caused by excessive lipid peroxidation, and it plays a vital role in the occurrence and development of liver fibrosis. In the present study, we aimed to study the proferroptosis effect and mechanism of MSC-ex in HSCs. MSC-ex were collected and purified from human umbilical cord MSCs. Proferroptosis effect of MSC-ex was examined in HSCs line LX-2 and CCl4 induced liver fibrosis in mice. Gene knockdown or overexpression approaches were used to investigate the biofactors in MSC-ex-mediated ferroptosis regulation. Results: MSC-ex could trigger HSCs ferroptosis by promoting ferroptosis-like cell death, ROS formation, mitochondrial dysfunction, Fe2+ release, and lipid peroxidation in human HSCs line LX-2. Glutathione peroxidase 4 (GPX4) is a crucial regulator of ferroptosis. We found that intravenous injection of MSC-ex significantly decreased glutathione peroxidase 4 (GPX4) expression in activated HSCs and collagen deposition in experimental mouse fibrotic livers. Mechanistically, MSC-ex derived BECN1 promoted HSCs ferroptosis by suppressing xCT-driven GPX4 expression. In addition, ferritinophagy and necroptosis might also play a role in MSC-ex-promoted LX-2 cell death. Knockdown of BECN1 in MSC diminished proferroptosis and anti-fibrosis effects of MSC-ex in LX-2 and fibrotic livers. MSC-ex may promote xCT/GPX4 mediated HSCs ferroptosis through the delivery of BECN1 and highlights BECN1 as a potential biofactor for alleviating liver fibrosis.
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- 2022
15. Exosome‐mediated effects and applications in inflammatory bowel disease
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Fei Mao, Xu Zhang, Wenrong Xu, Li Zhang, Dickson K. W. Ocansey, Yongmin Yan, Hui Qian, and Yifei Wang
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0106 biological sciences ,Gut flora ,medicine.disease_cause ,Exosomes ,010603 evolutionary biology ,01 natural sciences ,Exosome ,Inflammatory bowel disease ,digestive system ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Immune system ,inflammatory bowel disease ,intestinal mucosal barrier ,medicine ,exosome ,Humans ,030304 developmental biology ,Inflammation ,0303 health sciences ,therapy ,biology ,gut microbiota ,business.industry ,Original Articles ,Immune dysregulation ,biology.organism_classification ,medicine.disease ,Inflammatory Bowel Diseases ,microenvironment ,Microvesicles ,Gastrointestinal Microbiome ,immune system cells ,Immunology ,Dysbiosis ,Original Article ,Nanocarriers ,General Agricultural and Biological Sciences ,business - Abstract
Gut mucosal barriers, including chemical and physical barriers, spatially separate the gut microbiota from the host immune system to prevent unwanted immune responses that could lead to intestinal inflammation. In inflammatory bowel disease (IBD), there is mucosal barrier dysfunction coupled with immune dysregulation and dysbiosis. The discovery of exosomes as regulators of vital functions in both physiological and pathological processes has generated much research interest. Interestingly, exosomes not only serve as natural nanocarriers for the delivery of functional RNAs, proteins, and synthetic drugs or molecules, but also show potential for clinical applications in tissue repair and regeneration as well as disease diagnosis and prognosis. Biological or chemical modification of exosomes can broaden, change and enhance their therapeutic capability. We review the modulatory effects of exosomal proteins, RNAs and lipids on IBD components such as immune cells, the gut microbiota and the intestinal mucosal barrier. Mechanisms involved in regulating these factors towards attenuating IBD have been explored in several studies employing exosomes derived from different sources. We discuss the potential utility of exosomes as diagnostic markers and drug delivery systems, as well as the application of modified exosomes in IBD.
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- 2020
16. hucMSC-Derived Exosomes Alleviate the Deterioration of Colitis via the miR-146a/SUMO1 Axis
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Jingyan Wang, Bing Pei, Jialai Yan, Xinwei Xu, An-Ning Fang, Dickson Kofi Wiredu Ocansey, Xu Zhang, Hui Qian, Wenrong Xu, and Fei Mao
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Mice ,MicroRNAs ,Drug Discovery ,SUMO-1 Protein ,Pharmaceutical Science ,Molecular Medicine ,Animals ,Mesenchymal Stem Cells ,Colitis ,Exosomes ,Signal Transduction ,Umbilical Cord - Abstract
Human umbilical cord mesenchymal stem cell-derived exosome (hucMSC-Ex) plays an important role in tissue repair and immunomodulation, leading to the mitigation of inflammatory bowel disease. However, the preventive function of hucMSC-Ex in the onset and progression of colitis-associated colon cancer (CAC) is poorly understood. In the current study, dextran sodium sulfate/azoxymethane-induced colitis mouse model was established, and the mice disease activity index, body weight, colon length, tumor counts, survival curve, tissue HE/immunohistochemistry, and cytokines expression were analyzed to evaluate the effects of hucMSC-Ex on CAC. In addition, miR-146a mimics were transfected into colonic epithelial cells (fetal human cells) to evaluate their role in the hucMSC-Ex-mediated regulation of SUMO1. The results showed that hucMSC-Ex inhibits the expression of SUMO1 to reduce the process of CAC progression. Further analysis indicated that miR-146a targets and inhibits SUMO1 expression and its binding to β-catenin. In conclusion, our findings showed that hucMSC-Ex is effective in alleviating the deterioration of colitis via the miR-146a-mediated inhibition of SUMO1, which is crucial in this disease process.
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- 2022
17. Exosomes: Emerging Cell-Free Based Therapeutics in Dermatologic Diseases
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Yaoxiang Sun, Wenrong Xu, Dakai Yang, Min Wang, Hui Qian, and Hui Shi
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Cell signaling ,bioengineering ,QH301-705.5 ,Chemistry ,cell communication ,Review ,exosomes ,Cell Biology ,Cell free ,Microvesicles ,Cell biology ,Cell and Developmental Biology ,cell-free therapy ,Dermatologic diseases ,Biology (General) ,dermatologic diseases ,Developmental Biology - Abstract
Exosomes are lipid bilayer vesicles released by multiple cell types. These bioactive vesicles are gradually becoming a leading star in intercellular communication involving in various pathological and physiological process. Exosomes convey specific and bioactive transporting cargos, including lipids, nucleic acids and proteins which can be reflective of their parent cells, rendering them attractive in cell-free therapeutics. Numerous findings have confirmed the crucial role of exosomes in restraining scars, burning, senescence and wound recovery. Moreover, the biology research of exosomes in cutting-edge studies are emerging, allowing for the development of particular guidelines and quality control methodology, which favor their possible application in the future. In this review, we discussed therapeutic potential of exosomes in different relevant mode of dermatologic diseases, as well as the various molecular mechanisms. Furthermore, given the advantages of favorable biocompatibility and transporting capacity, the bioengineering modification of exosomes is also involved.
- Published
- 2021
18. hucMSC-derived exosomes attenuate colitis by regulating macrophage pyroptosis via the miR-378a-5p/NLRP3 axis
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Jintao Yuan, Qiang Tu, Wei Qiu, Dickson Kofi Wiredu Ocansey, Zhi-yu Zhang, Xiu Cai, Fei Mao, Wenrong Xu, Xu Zhang, and Hui Qian
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0301 basic medicine ,Medicine (General) ,Macrophage ,IBD ,Cell ,Medicine (miscellaneous) ,Inflammation ,QD415-436 ,Exosomes ,Biochemistry ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Inflammatory bowel disease ,Umbilical Cord ,Mice ,03 medical and health sciences ,R5-920 ,0302 clinical medicine ,NLRP3 ,NLR Family, Pyrin Domain-Containing 3 Protein ,Pyroptosis ,medicine ,Animals ,Colitis ,hucMSC-derived exosomes ,Mice, Inbred BALB C ,Chemistry ,Research ,Macrophages ,Cell Biology ,miR-378a-5p ,medicine.disease ,Microvesicles ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Molecular Medicine ,Stem cell ,medicine.symptom - Abstract
Background Human umbilical cord mesenchymal stem cell (hucMSC)-derived exosomes are recognized as novel cell-free therapeutic agents for inflammatory bowel disease (IBD), a condition caused by dysregulated intestinal mucosal immunity. In this event, macrophage pyroptosis, a process of cell death following the activation of NLRP3 (NOD-like receptor family, pyrin domain-containing 3) inflammasomes, is believed to partially account for inflammatory reactions. However, the role of macrophage pyroptosis in the process of hucMSC-derived exosomes alleviating colitis remains unknown. This study aimed at exploring the therapeutic effect and mechanism of hucMSC-derived exosomes on colitis repair. Methods In vivo, we used BALB/c mice to establish a dextran sulfate sodium (DSS)-induced colitis model and administrated hucMSC-derived exosomes intravenously to estimate its curative effect. Human myeloid leukemia mononuclear (THP-1) cells and mouse peritoneal macrophages (MPMs) were stimulated with lipopolysaccharides (LPS) and Nigericin to activate NLRP3 inflammasomes, which simulated an inflammation environment in vitro. A microRNA mimic was used to verify the role of miR-378a-5p/NLRP3 axis in the colitis repair. Results hucMSC-derived exosomes inhibited the activation of NLRP3 inflammasomes in the mouse colon. The secretion of interleukin (IL)-18, IL-1β, and Caspase-1 cleavage was suppressed, resulting in reduced cell pyroptosis. The same outcome was observed in the in vitro cell experiments, where the co-culture of THP-1 cells and MPMs with hucMSC-derived exosomes caused decreased expression of NLRP3 inflammasomes and increased cell survival. Furthermore, miR-378a-5p was highly expressed in hucMSC-derived exosomes and played a vital function in colitis repair. Conclusion hucMSC-derived exosomes carrying miR-378a-5p inhibited NLRP3 inflammasomes and abrogated cell pyroptosis to protect against DSS-induced colitis.
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- 2021
19. Emerging Role of Mesenchymal Stem Cell-derived Exosomes in Regenerative Medicine
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Hui Qian, Yongmin Yan, Ting Zhao, Fei Mao, Jinwen Liu, Feng Sun, Tianyan Ding, Wenrong Xu, and Jie She
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business.industry ,Regeneration (biology) ,Mesenchymal stem cell ,Cell- and Tissue-Based Therapy ,Medicine (miscellaneous) ,Mesenchymal Stem Cells ,General Medicine ,Extracellular vesicle ,Exosomes ,Regenerative Medicine ,Exosome ,Regenerative medicine ,Microvesicles ,Cell therapy ,Paracrine signalling ,Cancer research ,Animals ,Humans ,Medicine ,business - Abstract
Background:Recent studies have shown the great value of cell therapy over the past few decades. Mesenchymal stem cells (MSCs) have been reported to treat various degenerative diseases not through their differentiation potential but through their paracrine factors of the extracellular vesicle (EV) including exosomes. Exosomes are nanosized (70~150 nm) membrane-bound extracellular vesicles, not only involved in cell-to-cell communication but also in the development of tissue injury repair.Objective:As more researchers proved the enormous potential of exosomes in the field of repairing damaged tissue currently, it is urgent to explore the concrete mechanism and make exosomes to be a practical treatment tool in clinical medicine. In our study, we analyzed and summarized the work on tissue repair via exosomes in order to give some suggestions about the application of exosomes in clinical reality in the future.Results:MSC-derived exosomes (MSC-Ex) contain a wide variety of functional proteins, mRNAs, miRNAs and signaling lipids. Compared with their parent cells, MSC-Ex are more stable and can reduce the inherent safety risks in administering viable cells such as the risk of occlusion in microvasculature. MSC-Ex can be used to develop a cell-free exosome-based therapy for regenerative medicine, and may provide an alternative to MSC-based therapy.Conclusion:This review summarizes the most recent knowledge of therapeutic potential of MSC-Ex in the liver, heart, kidney, bone, brain diseases and cancer, as well as their associated challenges and opportunities.
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- 2019
20. Exosomes derived from autologous dermal fibroblasts promote diabetic cutaneous wound healing through the Akt/β-catenin pathway
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Cheng Ji, Xinye Han, Yi Wang, Hui Shi, Hassan Mohamud Sahal, Peipei Wu, Jiahui Zhang, Qichen Wang, Hui Qian, Wenrong Xu, and Linli Li
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0301 basic medicine ,Male ,Angiogenesis ,Inflammation ,Biology ,Exosomes ,Umbilical vein ,Diabetes Mellitus, Experimental ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,medicine ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,Autografts ,Molecular Biology ,Protein kinase B ,Wnt Signaling Pathway ,Wound Healing ,integumentary system ,Regeneration (biology) ,Type 2 Diabetes Mellitus ,Cell Biology ,Fibroblasts ,Streptozotocin ,medicine.disease ,Rats ,030104 developmental biology ,Animals, Newborn ,Diabetes Mellitus, Type 2 ,030220 oncology & carcinogenesis ,Cancer research ,medicine.symptom ,Proto-Oncogene Proteins c-akt ,Developmental Biology ,medicine.drug ,Research Paper - Abstract
Diabetic cutaneous wounds are one of the complications of diabetes mellitus (DM) and are difficult to cure at present. Autologous dermal fibroblasts (DFs) have shown great promise in skin regeneration and repair. However, whether exosomes derived from autologous dermal fibroblasts (DF-Ex) can be used to accelerate diabetic cutaneous wound healing is unclear. In this study, human umbilical vein endothelial cells (HUVECs) were treated with high glucose. We found that DF-Ex could reverse the damage produced by high glucose in HUVECs in vitro. A high-fat diet and streptozotocin were used to establish a rat model of type 2 diabetes mellitus (T2DM), and a diabetic cutaneous wound model was established in the T2DM rats. We discovered that subcutaneous injections of DF-Ex could significantly promote re-epithelialization, collagen deposition, skin cell proliferation, angiogenesis and inhibit inflammation to accelerate diabetic cutaneous wound healing. We further explored the underlying mechanism and found that DF-Ex exerted positive effects by activating the Akt/β-catenin pathway. This research revealed that DF-Ex may provide a new treatment strategy for diabetic cutaneous wound healing.
- Published
- 2021
21. HucMSC exosome-delivered 14-3-3ζ alleviates ultraviolet radiation-induced photodamage via SIRT1 pathway modulation
- Author
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Peipei Wu, Bin Zhang, Zixuan Sun, Xinru Zhou, Hui Qian, Yaoxiang Sun, Wenrong Xu, Xinye Han, Qian Jin, Peiwen Fu, and Linli Li
- Subjects
Aging ,DNA damage ,Ultraviolet Rays ,exosomes ,medicine.disease_cause ,Exosome ,Umbilical Cord ,SIRT1 ,Western blot ,Sirtuin 1 ,In vivo ,medicine ,Autophagy ,Animals ,HaCaT Cells ,Humans ,Skin ,mesenchymal stem cells ,biology ,medicine.diagnostic_test ,Chemistry ,Cell Biology ,Hydrogen Peroxide ,Cell biology ,Rats ,Skin Aging ,HaCaT ,Disease Models, Animal ,Oxidative Stress ,14-3-3 Proteins ,Apoptosis ,Gene Knockdown Techniques ,biology.protein ,Female ,Oxidative stress ,Signal Transduction ,Research Paper - Abstract
Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-ex) are nano-sized membrane-bound vesicles that have been reported to facilitate skin regeneration and repair. However, the roles played by hucMSC-ex in ultraviolet (UV) radiation-induced skin photodamage and the underlying mechanisms remain unknown. To investigate the functions of hucMSC-ex in a rat model of acute skin photodamage, immunofluorescence and immunohistochemical staining, quantitative real-time-polymerase chain reaction (qRT-PCR), western blot, and gene silencing assays were performed. We found that the in vivo subcutaneous injection of hucMSC-ex elicited antioxidant and anti-inflammatory effects against UV radiation-induced DNA damage and apoptosis. Further studies showed that the sirtuin 1 (SIRT1) expression level in skin keratinocytes (HaCaT) decreased in a time- and dose-dependent manner under in vitro UV radiation induced-oxidative stress conditions, which could be reversed by treatment with hucMSC-ex. The activation of SIRT1 significantly attenuated UV- and H2O2-induced cytotoxic damage by inhibiting oxidative stress and promoting the activation of autophagy. Our study found that 14-3-3ζ protein, which was delivered by hucMSC-ex, exerted a cytoprotective function via the modulation of a SIRT1-dependent antioxidant pathway. Collectively, our findings indicated that hucMSC-ex might represent a new potential agent for preventing or treating UV radiation-induced skin photodamage and aging.
- Published
- 2020
22. Exosomes derived from hucMSC attenuate renal fibrosis through CK1δ/β-TRCP-mediated YAP degradation
- Author
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Yuan Zhu, Fengtian Sun, Leilei Zhang, Hui Shi, Qiongni Wang, Siqi Yin, Jiahui Zhang, Xu Zhang, Cheng Ji, Yongmin Yan, Hui Qian, and Wenrong Xu
- Subjects
0301 basic medicine ,Cancer Research ,Immunology ,Exosomes ,Kidney ,urologic and male genital diseases ,Article ,Umbilical Cord ,Rats, Sprague-Dawley ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Ubiquitin ,Fibrosis ,medicine ,Renal fibrosis ,Obstructive nephropathy ,Animals ,Humans ,lcsh:QH573-671 ,Gene knockdown ,biology ,lcsh:Cytology ,Chemistry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,YAP-Signaling Proteins ,Cell Biology ,beta-Transducin Repeat-Containing Proteins ,medicine.disease ,Biomechanical Phenomena ,Ubiquitin ligase ,Disease Models, Animal ,Mechanisms of disease ,030104 developmental biology ,medicine.anatomical_structure ,Casein Kinase Idelta ,Gene Knockdown Techniques ,030220 oncology & carcinogenesis ,Proteolysis ,biology.protein ,Cancer research ,Casein kinase 1 ,Apoptosis Regulatory Proteins ,Ureteral Obstruction - Abstract
Exosomes from human umbilical cord mesenchymal stem cells (hucMSC-Ex) have been suggested as novel nanomaterials for regenerative medicine. Here we explored the roles of hucMSC-Ex through regulating Yes-associated protein (YAP) in renal injury repair by using rat unilateral ureteral obstruction (UUO) models. Our study identified mechanical stress induced YAP nucleus expression and stimulated collagen deposition and interstitial fibrosis in the kidney. Then, infusion with hucMSC-Ex promoted YAP nuclear cytoplasmic shuttling and ameliorated renal fibrosis in UUO model. Interestingly, hucMSC-Ex delivered casein kinase 1δ (CK1δ) and E3 ubiquitin ligase β-TRCP to boost YAP ubiquitination and degradation. Knockdown of CK1δ and β-TRCP in hucMSC decreased the repairing effects of hucMSC-Ex on renal fibrosis. Our results suggest that hucMSC-Ex attenuates renal fibrosis through CK1δ/β-TRCP inhibited YAP activity, unveiling a new mechanism for the therapeutic effects of hucMSC-Ex on tissue injury and offering a potential approach for renal fibrosis treatment.
- Published
- 2020
23. Exosome-transmitted lncRNA UFC1 promotes non-small-cell lung cancer progression by EZH2-mediated epigenetic silencing of PTEN expression
- Author
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Fei Mao, Taofeng Zhu, Yanke Chen, Yu Zhang, Xueying Xu, Jiayin Zhang, Jianmei Gu, Hui Shi, Wenrong Xu, Xueyan Zang, Hui Qian, Sinan Hou, and Xu Zhang
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Lung Neoplasms ,Cell cycle checkpoint ,Exosomes ,Epigenesis, Genetic ,Mice ,0302 clinical medicine ,Cell Movement ,Carcinoma, Non-Small-Cell Lung ,Mice, Inbred BALB C ,Gene knockdown ,lcsh:Cytology ,EZH2 ,Up-Regulation ,030220 oncology & carcinogenesis ,Disease Progression ,Heterografts ,RNA, Long Noncoding ,Immunology ,Mice, Nude ,Biology ,Transfection ,Exosome ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Downregulation and upregulation ,Cell Line, Tumor ,Animals ,Humans ,Gene silencing ,PTEN ,Enhancer of Zeste Homolog 2 Protein ,Neoplasm Invasiveness ,lcsh:QH573-671 ,neoplasms ,Cell Proliferation ,PTEN Phosphohydrolase ,Diagnostic markers ,Cell Biology ,Microvesicles ,respiratory tract diseases ,Disease Models, Animal ,030104 developmental biology ,A549 Cells ,Case-Control Studies ,Ubiquitin-Conjugating Enzymes ,Cancer research ,biology.protein ,Non-small-cell lung cancer - Abstract
Long non-coding RNAs (LncRNAs) have been suggested as important regulators of cancer development and progression in non-small cell lung cancer (NSCLC). Nevertheless, the biological roles and clinical significance of lncRNA UFC1 in NSCLC remain unclear. We detected the expression of UFC1 in tumor tissues, serum, and serum exosomes of NSCLC patients by qRT-PCR. Gene overexpression or silencing were used to examine the biological roles of UFC1 in NSCLC. RNA immunoprecipitation and ChIP assays were performed to evaluate the interaction between UFC1 and enhancer of zeste homolog 2 (EZH2) and the binding of EZH2 to PTEN gene promoter. Rescue study was used to access the importance of PTEN regulation by UFC1 in NSCLC progression. UFC1 expression was upregulated in tumor tissues, serum, and serum exosomes of NSCLC patients and high level of UFC1 was associated with tumor infiltration. UFC1 knockdown inhibited NSCLC cell proliferation, migration and invasion while promoted cell cycle arrest and apoptosis. UFC1 overexpression led to the opposite effects. Mechanistically, UFC1 bound to EZH2 and mediated its accumulation at the promoter region of PTEN gene, resulting in the trimethylation of H3K27 and the inhibition of PTEN expression. UFC1 knockdown inhibited NSCLC growth in mouse xenograft tumor models while the simultaneous depletion of PTEN reversed this effect. NSCLC cells derived exosomes could promote NSCLC cell proliferation, migration and invasion through the transfer of UFC1. Moreover, Exosome-transmitted UFC1 promotes NSCLC progression by inhibiting PTEN expression via EZH2-mediated epigenetic silencing. Exosome-mediated transmit of UFC1 may represent a new mechanism for NSCLC progression and provide a potential marker for NSCLC diagnosis.
- Published
- 2020
24. Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration
- Author
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Wenrong Xu, Hui Qian, Hui Shi, Pengcheng Jiang, Xiao Yuan, and Xu Zhang
- Subjects
0301 basic medicine ,Cancer Research ,Neutrophils ,Activation ,chemical and pharmacologic phenomena ,Biology ,Exosomes ,HMGB1 ,Models, Biological ,Exosome ,lcsh:RC254-282 ,Neutrophil Activation ,03 medical and health sciences ,Cell Movement ,Stomach Neoplasms ,Cell Line, Tumor ,Pro-tumor ,medicine ,Autophagy ,Humans ,Gene silencing ,HMGB1 Protein ,Tumor microenvironment ,Research ,Macrophages ,Neutrophil ,NF-kappa B ,Cell Polarity ,Cancer ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Microvesicles ,Toll-Like Receptor 4 ,030104 developmental biology ,Oncology ,Culture Media, Conditioned ,Gene Knockdown Techniques ,Cancer cell ,biology.protein ,Cancer research ,Molecular Medicine ,Gastric cancer ,Protein Binding ,Signal Transduction - Abstract
Background Exosomes are extracellular vesicles that mediate cellular communication in health and diseases. Neutrophils could be polarized to a pro-tumor phenotype by tumor. The function of tumor-derived exosomes in neutrophil regulation remains unclear. Methods We investigated the effects of gastric cancer cell-derived exosomes (GC-Ex) on the pro-tumor activation of neutrophils and elucidated the underlying mechanisms. Results GC-Ex prolonged neutrophil survival and induced expression of inflammatory factors in neutrophils. GC-Ex-activated neutrophils, in turn, promoted gastric cancer cell migration. GC-Ex transported high mobility group box-1 (HMGB1) that activated NF-κB pathway through interaction with TLR4, resulting in an increased autophagic response in neutrophils. Blocking HMGB1/TLR4 interaction, NF-κB pathway, and autophagy reversed GC-Ex-induced neutrophil activation. Silencing HMGB1 in gastric cancer cells confirmed HMGB1 as a key factor for GC-Ex-mediated neutrophil activation. Furthermore, HMGB1 expression was upregulated in gastric cancer tissues. Increased HMGB1 expression was associated with poor prognosis in patients with gastric cancer. Finally, gastric cancer tissue-derived exosomes acted similarly as exosomes derived from gastric cancer cell lines in neutrophil activation. Conclusion We demonstrate that gastric cancer cell-derived exosomes induce autophagy and pro-tumor activation of neutrophils via HMGB1/TLR4/NF-κB signaling, which provides new insights into mechanisms for neutrophil regulation in cancer and sheds lights on the multifaceted role of exosomes in reshaping tumor microenvironment. Electronic supplementary material The online version of this article (10.1186/s12943-018-0898-6) contains supplementary material, which is available to authorized users.
- Published
- 2018
25. UBR2 Enriched in p53 Deficient Mouse Bone Marrow Mesenchymal Stem Cell-Exosome Promoted Gastric Cancer Progression via Wnt/β-Catenin Pathway
- Author
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Hailong Fu, Zhaofeng Liang, Jiahui Mao, Yongmin Yan, Xia Li, Hui Qian, Wenrong Xu, Xu Zhang, Huan Yang, and Bin Zhang
- Subjects
0301 basic medicine ,Homeobox protein NANOG ,Ubiquitin-Protein Ligases ,Exosomes ,Exosome ,Mice ,03 medical and health sciences ,Stomach Neoplasms ,Cell Line, Tumor ,Animals ,Humans ,Wnt Signaling Pathway ,beta Catenin ,Cell Proliferation ,Tumor microenvironment ,biology ,CD44 ,Mesenchymal stem cell ,Wnt signaling pathway ,Cell Differentiation ,Mesenchymal Stem Cells ,LRP5 ,Cell Biology ,030104 developmental biology ,Disease Progression ,Cancer research ,biology.protein ,Molecular Medicine ,Stem cell ,Developmental Biology - Abstract
The deficiency or mutation of p53 has been linked to several types of cancers. The mesenchymal stem cell (MSC) is an important component in the tumor microenvironment, and exosomes secreted by MSCs can transfer bioactive molecules, including proteins and nucleic acid, to other cells in the tumor microenvironment to influence the progress of a tumor. However, whether the state of p53 in MSCs can impact the bioactive molecule secretion of exosomes to promote cancer progression and the regulatory mechanism remains elusive. Our study aimed to investigate the regulation of ubiquitin protein ligase E3 component n-recognin 2 (UBR2) enriched in exosomes secreted by p53 deficient mouse bone marrow MSC (p53–/–mBMMSC) in gastric cancer progression in vivo and in vitro. We found that the concentration of exosome was significantly higher in p53–/–mBMMSC than that in p53 wild-type mBMMSC (p53+/+mBMMSC). In particular, UBR2 was highly expressed in p53–/–mBMMSC cells and exosomes. P53–/–mBMMSC exosomes enriched UBR2 could be internalized into p53+/+mBMMSC and murine foregastric carcinoma (MFC) cells and induce the overexpression of UBR2 in these cells which elevated cell proliferation, migration, and the expression of stemness-related genes. Mechanistically, the downregulation of UBR2 in p53–/–mBMMSC exosomes could reverse these actions. Moreover, a majority of Wnt family members, β-catenin, and its downstream genes (CD44, CyclinD1, CyclinD3, and C-myc) were significantly decreased in MFC knockdown UBR2 and β-catenin depletion, an additional depletion of UBR2 had no significant difference in the expression of Nanog, OCT4, Vimentin, and E-cadherin. Taken together, our findings indicated that p53–/–mBMMSC exosomes could deliver UBR2 to target cells and promote gastric cancer growth and metastasis by regulating Wnt/β-catenin pathway.
- Published
- 2017
26. Exosomes-mediated transfer of long noncoding RNA ZFAS1 promotes gastric cancer progression
- Author
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Wei Liang, Pengcheng Jiang, Wenrong Xu, Lei Pan, Xu Zhang, Xia Li, Zhenhua Huang, Hui Qian, Min Fu, Peng Zhang, and Wen Zhang
- Subjects
Adult ,Male ,0301 basic medicine ,Cancer Research ,Epithelial-Mesenchymal Transition ,Cell ,Biology ,Exosomes ,RNA Transport ,Flow cytometry ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Western blot ,Cell Movement ,Stomach Neoplasms ,Biomarkers, Tumor ,Tumor Cells, Cultured ,medicine ,Humans ,Neoplasm Invasiveness ,Aged ,Cell Proliferation ,Aged, 80 and over ,Gene knockdown ,medicine.diagnostic_test ,Cell growth ,General Medicine ,Middle Aged ,Prognosis ,medicine.disease ,Molecular biology ,Microvesicles ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Disease Progression ,Cancer research ,Female ,RNA, Long Noncoding - Abstract
ZFAS1 is a newly identified long noncoding RNA (lncRNA) that promotes tumor growth and metastasis. Exosomes mediate cellular communications in cancer by transmitting active molecules. The presence of ZFAS1 in the circulating exosomes and the roles of exosomal ZFAS1 in gastric cancer (GC) remains unknown. The aim of this study was to investigate the potential roles of exosomal ZFAS1 in GC. The expression of ZFAS1 was examined in the tumor tissues, serum samples, serum exosomes of GC patients and cell lines using qRT-PCR. The correlation between ZFAS1 expression and the clinicopathological characteristics was analyzed. The characteristics of exosomes were identified using transmission electron microscope (TEM), Nanoparticle Tracking Analysis (NTA), and western blot. The biological roles of ZFAS1 in GC cell growth and mobility were investigated using cell counting, cell colony formation, and transwell migration assay. The potential mechanism of ZFAS1 was demonstrated using flow cytometry, western blot, and qRT-PCR. ZFAS1 expression was elevated in GC cells, tumor tissues, serum and serum exosomes of GC patients. The increased ZFAS1 expression was significantly correlated with lymphatic metastasis and TNM stage. ZFAS1 knockdown inhibited the proliferation and migration of GC cells by suppressing cell cycle progression, inducing apoptosis, and inhibiting epithelial-mesenchymal transition (EMT). On the contrary, ZFAS1 overexpression promoted the proliferation and migration of GC cells. Moreover, ZFAS1 was present in exosomes and could be transmitted by exosomes to enhance GC cell proliferation and migration. ZFAS1 could be delivered by exosomes to promote GC progression, which suggests that ZFAS1 may serve as a potential diagnostic and prognostic biomarker for GC.
- Published
- 2017
27. Human umbilical cord mesenchymal stem cell exosomes alleviate sepsis-associated acute kidney injury via regulating microRNA-146b expression
- Author
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Cheng Ji, Lei Yin, Xinru Zhou, Yuyan Hu, Rongxue Zhang, Siqi Yin, Jingyan Chen, Yuan Zhu, Wanzhu Liu, Qiongni Wang, Hui Qian, Wenrong Xu, and Yang Li
- Subjects
0106 biological sciences ,0301 basic medicine ,Male ,Bioengineering ,Pharmacology ,Exosomes ,01 natural sciences ,Applied Microbiology and Biotechnology ,Umbilical cord ,Blood Urea Nitrogen ,Cell Line ,Umbilical Cord ,Sepsis ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,010608 biotechnology ,medicine ,Animals ,Humans ,Blood urea nitrogen ,Kidney ,Creatinine ,business.industry ,Mesenchymal stem cell ,Acute kidney injury ,Interleukin ,Mesenchymal Stem Cells ,General Medicine ,Acute Kidney Injury ,medicine.disease ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Interleukin-1 Receptor-Associated Kinases ,chemistry ,Gene Expression Regulation ,Cisplatin ,business ,Biotechnology - Abstract
Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSC-Ex) are a promising tool for the repair of acute kidney injury (AKI) caused by cisplatin and ischemia/reperfusion. However, the roles of hucMSC-Ex in sepsis-associated AKI repair and its mechanism are largely unknown. Hence, we constructed a sepsis model through cecal ligation and puncture (CLP), testing the benefits of hucMSC-Ex in the sepsis in terms of survival rate, serum renal markers levels, morphological changes and apoptosis. Immunohistochemistry staining and immunofluorescence assay were used to investigate the role of NF-κB activity in the repair of sepsis-associated AKI with hucMSC-Ex. HK-2 cells were transfected with microRNA-146b (miR-146b) mimics and inhibitors, respectively, and the regulatory effect of miR-146b on NF-κB activity was studied. We found that hucMSC-Ex treatment significantly decreased the serum creatinine (Cr) and blood urea nitrogen (BUN) levels, ameliorated the morphological damage and inhibited renal tubular cells apoptosis. More importantly, the survival rate at 72 h was 28% in CLP group and 45% in hucMSC-Ex group, respectively. Treatment with hucMSC-Ex improved survival in mice with sepsis. These effects of hucMSC-Ex were mediated by the inhibition of NF-κB activity and the lessening of pro-inflammatory response. Furthermore, hucMSC-Ex significantly increased miR-146b expression in kidney tissues. Conversely, interleukin (IL)-1 receptor-associated kinase (IRAK1) level, which is the target gene of miR-146b, clearly decreased in hucMSC-Ex group. In brief, this study showed that treatment with hucMSC-Ex decreased IRAK1 expression through the up-regulation of miR-146b level, led to the inhibition of NF-κB activity, and eventually alleviated sepsis-associated AKI and improved survival in mice with sepsis. HucMSC-Ex may be a novel therapeutic agent for the reduction of sepsis-associated AKI.
- Published
- 2019
28. HucMSC Exosome-Delivered 14-3-3ζ Orchestrates Self-Control of the Wnt Response via Modulation of YAP During Cutaneous Regeneration
- Author
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Yongmin Yan, Zhaoji Pan, Hui Shi, Bin Zhang, Wenrong Xu, Yinghong Shi, Hailong Fu, Aihua Gong, Hui Qian, Xu Zhang, Wei Zhu, Huan Yang, and Mei Wang
- Subjects
0301 basic medicine ,Cell Count ,Protein Serine-Threonine Kinases ,Biology ,Exosomes ,Exosome ,Cell Line ,Substrate Specificity ,Umbilical Cord ,03 medical and health sciences ,WNT4 ,Serine ,Humans ,Regeneration ,Phosphorylation ,Wnt Signaling Pathway ,beta Catenin ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Skin ,Regeneration (biology) ,Mesenchymal stem cell ,Wnt signaling pathway ,Mesenchymal Stem Cells ,YAP-Signaling Proteins ,Cell Biology ,Anatomy ,Phosphoproteins ,Microvesicles ,Cell biology ,Wnt Proteins ,Protein Transport ,030104 developmental biology ,14-3-3 Proteins ,Molecular Medicine ,Collagen ,Stem cell ,Protein Binding ,Transcription Factors ,Developmental Biology - Abstract
Numerous studies showed that mesenchymal stem cells derived exosome (MSC-Ex) markedly enhanced tissue regeneration, however, the issue of whether MSC-Ex could control stem cells expansion after a regenerative response to prevent tissue from overcrowding and dysplasia remains to be established. Herein, we found that human umbilical cord MSC (hucMSC)-exosomal14-3-3ζ mediated the binding of YAP and p-LATS by forming a complex to promote the phosphorylation of YAP, which orchestrate exosomal Wnt4 signal in cutaneous regeneration. First, we assessed deep second-degree burn rats treated with hucMSC-Ex and discovered that hucMSC-Ex promoting self-regulation of Wnt/β-catenin signaling at the remodeling phase of cutaneous regeneration. HucMSC-Ex restricted excessive skin cell expansion and collagen deposition at 4 weeks. Under high cell density conditions, hucMSC-Ex inhibited Wnt/β-catenin signaling through induction of YAP phosphorylation. Second, hucMSC-Ex proteomic analysis revealed that 14-3-3 proteins could be transported by exosome. Using gain- and loss-of-function studies, our results showed that hucMSC-exosomal 14-3-3ζ controlled YAP activities and phosphorylation at Ser127 site, and were required for the binding of YAP and p-LATS. Further studies revealed that 14-3-3ζ recruited YAP and p-LATS to form a complex under high cells density status and 14-3-3ζ other than YAP or p-LATS was the key regulatory molecule of this complex. These findings collectively indicate that hucMSC-Ex functions not only as an “accelerator” of the Wnt/β-catenin signal to repair damaged skin tissue but also as a “brake” of the signal by modulating YAP to orchestrate controlled cutaneous regeneration.
- Published
- 2016
29. Human Mesenchymal Stem Cell Derived Exosomes Alleviate Type 2 Diabetes Mellitus by Reversing Peripheral Insulin Resistance and Relieving β-Cell Destruction
- Author
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Siqi Yin, Cheng Ji, Bin Zhang, Peipei Wu, Fei Mao, Yaoxiang Sun, Hui Shi, Yinghong Shi, Wenrong Xu, Hui Qian, Yongmin Yan, and Xu Zhang
- Subjects
0301 basic medicine ,Male ,endocrine system diseases ,General Physics and Astronomy ,Apoptosis ,Pharmacology ,Exosomes ,Streptozocin ,Diabetes Mellitus, Experimental ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,Insulin resistance ,Insulin-Secreting Cells ,medicine ,Glucose homeostasis ,Animals ,Humans ,General Materials Science ,Protein kinase B ,Glycogen ,business.industry ,Mesenchymal stem cell ,General Engineering ,Glucose transporter ,nutritional and metabolic diseases ,Type 2 Diabetes Mellitus ,Mesenchymal Stem Cells ,medicine.disease ,IRS1 ,Rats ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Diabetes Mellitus, Type 2 ,Insulin Resistance ,business - Abstract
Exosomes are nanosized extracellular vesicles (EVs) that show great promise in tissue regeneration and injury repair as mesenchymal stem cell (MSC). MSC has been shown to alleviate diabetes mellitus (DM) in both animal models and clinical trials. In this study, we aimed to investigate whether exosomes from human umbilical cord MSC (hucMSC-ex) have a therapeutic effect on type 2 DM (T2DM). We established a rat model of T2DM using a high-fat diet and streptozotocin (STZ). We found that the intravenous injection of hucMSC-ex reduced blood glucose levels as a main paracrine approach of MSC. HucMSC-ex partially reversed insulin resistance in T2DM indirectly to accelerate glucose metabolism. HucMSC-ex restored the phosphorylation (tyrosine site) of the insulin receptor substrate 1 and protein kinase B in T2DM, promoted expression and membrane translocation of glucose transporter 4 in muscle, and increased storage of glycogen in the liver to maintain glucose homeostasis. HucMSC-ex inhibited STZ-induced β-cell apoptosis to restore the insulin-secreting function of T2DM. Taken together, exosomes from hucMSC can alleviate T2DM by reversing peripheral insulin resistance and relieving β-cell destruction, providing an alternative approach for T2DM treatment.
- Published
- 2018
30. Exosomal TRIM3 is a novel marker and therapy target for gastric cancer
- Author
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Xu Zhang, Huan Yang, Zixuan Sun, Bin Zhang, Jiahui Mao, Mei Wang, Xia Li, Hui Qian, Bo Wang, Wenrong Xu, and Hailong Fu
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Exosomes ,Transfection ,lcsh:RC254-282 ,Metastasis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Stomach Neoplasms ,In vivo ,Cell Line, Tumor ,Diagnosis ,medicine ,Animals ,Humans ,TRIM3 ,Gene knockdown ,Progression ,business.industry ,Research ,digestive, oral, and skin physiology ,Cancer ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Microvesicles ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Disease Progression ,Cancer research ,Immunohistochemistry ,Cancer biomarkers ,Therapy ,Carrier Proteins ,Gastric cancer ,business - Abstract
Background Exosomes are critically involved in cancer development and progression. The exosomal contents have been suggested as ideal cancer biomarkers. In this study, we investigated the expression of exosomal proteins in the serum of gastric cancer patients and their roles in gastric cancer. Methods The proteomic profile of exosomes from the serum of gastric cancer patients was detected by using LC-MS/MS. The expression of TRIM3 in exosomes from the serum of gastric cancer patients and healthy controls was assessed by ELISA and western blot. Immunohistochemistry was used to detect TRIM3 expression in gastric cancer tissues and their matching adjacent tissues. The growth and migration abilities of gastric cancer cells with TRIM3 overexpression or knockdown in vitro were evaluated by colony formation assay and transwell migration assay. The effects of TRIM3 overexpression or knockdown on gastric cancer growth and metastasis in vivo were investigated by using subcutaneous xenograft tumor and peritoneal metastasis mouse model. The effects of TRIM3-overexpressing exosomes on gastric cancer growth and metastasis in vitro and in vivo were also evaluated. Results We found that the expression levels of TRIM3 mRNA and protein were decreased in gastric cancer tissues compared to the matched control tissues. In addition, the levels of TRIM3 protein in the serum exosomes of gastric cancer patients were lower than that in healthy controls. We demonstrated that TRIM3 overexpression reduced while TRIM3 knockdown promoted the growth and metastasis of gastric cancer in vitro and in vivo through the regulation of stem cell factors and EMT regulators. Moreover, exosomes-mediated delivery of TRIM3 protein could suppress gastric cancer growth and metastasis in vitro and in vivo. Conclusions Taken together, our findings suggest that exosomal TRIM3 may serve as a biomarker for gastric cancer diagnosis and the delivery of TRIM3 by exosomes may provide a new avenue for gastric cancer therapy. Electronic supplementary material The online version of this article (10.1186/s13046-018-0825-0) contains supplementary material, which is available to authorized users.
- Published
- 2018
31. HucMSC-Exosome Mediated-Wnt4 Signaling Is Required for Cutaneous Wound Healing
- Author
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Wei Zhu, Wenrong Xu, Hui Qian, Yanhua Zhu, Lijun Wu, Xu Zhang, Bin Zhang, Mei Wang, Xiaodan Wu, Aihua Gong, and Hui Shi
- Subjects
Wound Healing ,Mesenchymal stem cell ,Wnt signaling pathway ,Mesenchymal Stem Cells ,Cell Biology ,Biology ,Exosomes ,Exosome ,Rats ,Cell biology ,Wnt4 Protein ,In vivo ,Immunology ,Animals ,Humans ,Molecular Medicine ,Stem cell ,Wound healing ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Signal Transduction ,Skin ,Developmental Biology - Abstract
Mesenchymal stem cell-derived exosomes (MSC-Ex) play important roles in tissue injury repair, however, the roles of MSC-Ex in skin damage repair and its mechanisms are largely unknown. Herein, we examined the benefit of human umbilical cord MSC-derived exosome (hucMSC-Ex) in cutaneous wound healing using a rat skin burn model. We found that hucMSC-Ex-treated wounds exhibited significantly accelerated re-epithelialization, with increased expression of CK19, PCNA, collagen I (compared to collagen III) in vivo. HucMSC-Ex promoted proliferation and inhibited apoptosis of skin cells after heat-stress in vitro. We also discovered that Wnt4 was contained in hucMSC-Ex, and hucMSC-Ex-derived Wnt4 promoted β-catenin nuclear translocation and activity to enhance proliferation and migration of skin cells, which could be reversed by β-catenin inhibitor ICG001. In vivo studies confirmed that the activation of Wnt/β-catenin by hucMSC-Ex played a key role in wound re-epithelialization and cell proliferation. Furthermore, knockdown of Wnt4 in hucMSC-Ex abrogated β-catenin activation and skin cell proliferation and migration in vitro. The in vivo therapeutic effects were also inhibited when the expression of Wnt4 in hucMSC-Ex was interfered. In addition, the activation of AKT pathway by hucMSC-Ex was associated with the reduction of heat stress-induced apoptosis in rat skin burn model. Collectively, our findings indicate that exosome-delivered Wnt4 provides new aspects for the therapeutic strategy of MSCs in cutaneous wound healing. Stem Cells 2015;33:2158–2168
- Published
- 2015
32. Exosomal miR-423-5p targets SUFU to promote cancer growth and metastasis and serves as a novel marker for gastric cancer
- Author
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Bo Wang, Xu Zhang, Hui Qian, Huan Yang, Zixuan Sun, Wenrong Xu, Jiahui Mao, Hailong Fu, Mei Wang, and Xia Li
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Biology ,Exosomes ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Stomach Neoplasms ,Cell Line, Tumor ,microRNA ,Gastric mucosa ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Neoplasm Metastasis ,Molecular Biology ,Cell Proliferation ,Mice, Inbred BALB C ,Cell growth ,digestive, oral, and skin physiology ,Cancer ,Middle Aged ,medicine.disease ,Prognosis ,Microvesicles ,Gene Expression Regulation, Neoplastic ,Repressor Proteins ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Cancer biomarkers ,Female ,Lymph Nodes - Abstract
Exosomes are critically involved in tumor growth, metastasis, and therapy resistance. Exosomes have the potential to be utilized as cancer biomarkers. In this study, we aimed to explore the roles and clinical values of exosomal miRNAs in gastric cancer. We found that the concentration of exosomes was significantly higher in the serum of gastric cancer patients and the culture supernatants of gastric cancer cells than that in healthy volunteers and gastric mucosa epithelial cells. In particular, miR-423-5p was elevated in the serum exosomes of gastric cancer patients, and the level of exosomal miR-423-5p was remarkably correlated with lymph node metastasis. High level of exosomal miR-423-5p was associated with poor outcome in gastric cancer patients. MiR-423-5p enriched exosomes could be internalized into gastric cancer cells, which enhanced cell proliferation and migration both in vitro and in vivo. Mechanistically, miR-423-5p inhibited the expression of suppressor of fused protein (SUFU) to enhance the proliferation and migration of gastric cancer cells. The expression levels of SUFU were significantly decreased in gastric cancer cells and the tumor tissues of gastric cancer patients. Taken together, our findings indicate that exosomes could deliver miR-423-5p to promote cancer growth and metastasis and serum exosomal miR-423-5p may serve as a potential marker for gastric cancer diagnosis and prognosis.
- Published
- 2017
33. MSC-exosome: A novel cell-free therapy for cutaneous regeneration
- Author
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Hui Shi, Wenrong Xu, Hui Qian, Peipei Wu, and Bin Zhang
- Subjects
0301 basic medicine ,Chronic wound ,Cancer Research ,Angiogenesis ,Immunology ,Exosomes ,Exosome ,Extracellular matrix ,03 medical and health sciences ,Skin Physiological Phenomena ,Immunology and Allergy ,Medicine ,Animals ,Humans ,Regeneration ,RNA, Messenger ,Genetics (clinical) ,Skin ,Transplantation ,Wound Healing ,Cell-Free System ,business.industry ,Regeneration (biology) ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Microvesicles ,Cell biology ,MicroRNAs ,030104 developmental biology ,Oncology ,medicine.symptom ,business ,Wound healing - Abstract
Cutaneous regeneration is a dynamic and complex process that requires a series of coordinated interactions involving epidermal cells, dermal cells, growth factors, the extracellular matrix (ECM), nerves and blood vessels at a damaged site. Mesenchymal stromal cells (MSCs) have been reported to participate in all afore-mentioned stages. Exosomes are one of the key secretory products of MSCs, resembling the effect of parental MSCs. They can shuttle various proteins, messenger RNA (mRNA) and microRNAs (miRNAs) to modulate the activity of recipient cells, and play important roles in cutaneous wound healing. Compared with MSCs, exosomes are more convenient to store and transport. Moreover, they avoid many risks associated with cell transplantation. Therefore, MSC-exosome-mediated therapy may be more safe and efficient. In this review, we summarize the latest studies and observations on the role of MSC-exosome in the acute and chronic wound model and provide a comprehensive understanding of the role of exosomes in wound healing. This review can assist investigators in exploring new therapeutic strategies for enhancing the efficacy of MSC-exosome for cutaneous repair and regeneration.
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- 2017
34. HucMSC exosome-transported 14-3-3ζ prevents the injury of cisplatin to HK-2 cells by inducing autophagy in vitro
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Jing Yu, Fei Mao, Juanjuan Wang, Bin Zhang, Yongmin Yan, Haoyuan Jia, Xiao Xu, Cheng Ji, Lei Yin, Wenrong Xu, and Hui Qian
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0301 basic medicine ,Cancer Research ,Stromal cell ,Immunology ,Exosomes ,Exosome ,Umbilical Cord ,03 medical and health sciences ,Western blot ,Autophagy ,Immunology and Allergy ,Medicine ,Animals ,Humans ,Genetics (clinical) ,Cisplatin ,Transplantation ,biology ,medicine.diagnostic_test ,business.industry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Proliferating cell nuclear antigen ,Rats ,030104 developmental biology ,HEK293 Cells ,Oncology ,Terminal deoxynucleotidyl transferase ,14-3-3 Proteins ,Apoptosis ,Gene Knockdown Techniques ,biology.protein ,Cancer research ,business ,medicine.drug - Abstract
Background aims On the basis of previous studies, exosomes secreted by human umbilical cord mesenchymal stromal cell (hucMSC-ex) could prevent and repair acute kidney injury induced by cisplatin in rats. However, its potential mechanism is still unclear. In the present study, the model with hucMSC-ex pretreated human renal tubular epithelial cell lines HK-2 that could prevent the injury of cisplatin was successfully established. Methods First, we pretreated the HK-2 cells with hucMSC-ex for 24 h. Cisplatin was then used to injure HK-2 cells. Gain and loss of function study were used to explore the role of 14-3-3ζ. The expression level of proliferating cell nuclear antigen (PCNA) was analyzed by immunofluorescence assay and Western blot. The number of apoptotic cells was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and flow cytometry analysis. The formation of autophagosomes was observed under super-resolution optical microscope. Western blot was used to analyze the expression levels of LC3B, P62, 14-3-3ζ and Bax. Results Pretreating cells with hucMSC-ex could prevent the injury of cisplatin by reducing the number of apoptotic cells and increasing the expression level of PCNA. Simultaneously, the autophagic level was up-regulated. The application of autophagic inhibitor 3-methyladenine (3-MA) could reverse the protective effect of hucMSC-ex. The overexpression of 14-3-3ζ enhanced the autophagic level and protected the injury of cisplatin. The knock-down of 14-3-3ζ could reduce the autophagic level and enhance the disadvantage of cisplatin. The enhanced injury of cisplatin was reversed when the knock-down of 14-3-3ζ was replenished with hucMSC-ex. Conclusions 14-3-3ζ transported by hucMSC-ex may up-regulate autophagic level in HK-2 cells, which can prevent the injury of cisplatin. This discovery provides the new theoretical basis for the prevention of cisplatin-induced nephrotoxicity by hucMSC-ex.
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- 2017
35. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Inflammatory Bowel Disease in Mice
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Jingjing Kang, Fei Mao, Yongmin Yan, Hui Qian, Xudong Tang, Yunbing Wu, Wenrong Xu, Xu Zhang, and Bin Zhang
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Article Subject ,Colon ,lcsh:Medicine ,Exosomes ,Inflammatory bowel disease ,Exosome ,Umbilical cord ,General Biochemistry, Genetics and Molecular Biology ,Umbilical Cord ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Colitis ,General Immunology and Microbiology ,business.industry ,Macrophages ,Dextran Sulfate ,Mesenchymal stem cell ,lcsh:R ,Mesenchymal Stem Cells ,General Medicine ,Inflammatory Bowel Diseases ,medicine.disease ,In vitro ,Microvesicles ,digestive system diseases ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cytokines ,business ,Infiltration (medical) ,Research Article - Abstract
Exosomes secreted by mesenchymal stem cells (MSCs) have shown repairing effects on several tissue injury diseases. In this study, we aimed to investigate the effects of exosomes released from human umbilical cord mesenchymal stem cells (hucMSCs) on the treatment of dextran sulfate sodium- (DSS-) induced inflammatory bowel disease (IBD) and to explore the underlying mechanism. We found that indocyanine green (ICG) labeled exosomes homed to colon tissues of IBD mice at 12 hours after injection. Exosomes significantly relieved the severity of IBD in mice as hucMSCs. The expression of IL-10 gene was increased while that of TNF-α, IL-1β, IL-6, iNOS, and IL-7 genes was decreased in the colon tissues and spleens of exosomes-treated mice. Furthermore, the infiltration of macrophages into the colon tissues was decreased by exosome treatment in IBD mice. In addition, we provided evidence that in vitro coculture with exosomes inhibited the expression of iNOS and IL-7 in mouse enterocoelia macrophages. Moreover, we found that the expression of IL-7 was higher in the colon tissues of colitis patients than that of healthy controls. Our findings suggest that exosomes from hucMSCs have profound effects on alleviating DSS-induced IBD and may exert their impact through the modulation of IL-7 expression in macrophages.
- Published
- 2017
36. Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Liver Fibrosis
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Yongmin Yan, Li Shen, Ying Zhou, Xu Zhang, Tingfen Li, Wenrong Xu, Mei Wang, Hui Qian, Bingying Wang, Wei Li, and Wei Zhu
- Subjects
Cell Extracts ,Liver Cirrhosis ,Epithelial-Mesenchymal Transition ,Cellular differentiation ,Smad Proteins ,Biology ,Exosomes ,Collagen Type I ,Cell Line ,Umbilical Cord ,Transforming Growth Factor beta1 ,Mice ,Liver disease ,Original Research Reports ,medicine ,Animals ,Humans ,Epithelial–mesenchymal transition ,Carbon Tetrachloride ,Cell Shape ,Mesenchymal stem cell ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,Hematology ,medicine.disease ,Transplantation ,Collagen Type III ,Liver ,Cell culture ,Immunology ,Cancer research ,Liver function ,Signal Transduction ,Developmental Biology ,Transforming growth factor - Abstract
Mesenchymal stem cells (MSCs) have been considered as an attractive tool for the therapy of diseases. Exosomes excreted from MSCs can reduce myocardial ischemia/reperfusion damage and protect against acute tubular injury. However, whether MSC-derived exosomes can relieve liver fibrosis and its mechanism remain unknown. Previous work showed that human umbilical cord-MSCs (hucMSCs) transplanted into acutely injured and fibrotic livers could restore liver function and improve liver fibrosis. In this study, it was found that transplantation of exosomes derived from hucMSC (hucMSC-Ex) reduced the surface fibrous capsules and got their textures soft, alleviated hepatic inflammation and collagen deposition in carbon tetrachloride (CCl4)-induced fibrotic liver. hucMSC-Ex also significantly recovered serum aspartate aminotransferase (AST) activity, decreased collagen type I and III, transforming growth factor (TGF)-β1 and phosphorylation Smad2 expression in vivo. In further experiments, we found that epithelial-to-mesenchymal transition (EMT)-associated markers E-cadherin-positive cells increased and N-cadherin- and vimentin-positive cells decreased after hucMSC-Ex transplantation. Furthermore, the human liver cell line HL7702 underwent typical EMT after induction with recombinant human TGF-β1, and then hucMSC-Ex treatment reversed spindle-shaped and EMT-associated markers expression in vitro. Taken together, these results suggest that hucMSC-Ex could ameliorate CCl4-induced liver fibrosis by inhibiting EMT and protecting hepatocytes. This provides a novel approach for the treatment of fibrotic liver disease.
- Published
- 2013
37. Pre-incubation with hucMSC-exosomes prevents cisplatin-induced nephrotoxicity by activating autophagy
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Cheng Ji, Jing Yu, Yongmin Yan, Lei Yin, Bingying Wang, Hui Qian, Juanjuan Wang, Haoyuan Jia, Wenrong Xu, Xueming Zhu, and Bin Zhang
- Subjects
0301 basic medicine ,Medicine (miscellaneous) ,Gene Expression ,Exosomes ,Autophagy-Related Protein 7 ,Autophagy-Related Protein 5 ,Umbilical Cord ,Rats, Sprague-Dawley ,0302 clinical medicine ,Renal capsule ,lcsh:QD415-436 ,Nephrotoxicity ,lcsh:R5-920 ,Nephritis ,Cell Differentiation ,medicine.anatomical_structure ,Human umbilical cord mesenchymal stem cell ,030220 oncology & carcinogenesis ,Molecular Medicine ,Female ,lcsh:Medicine (General) ,Microtubule-Associated Proteins ,medicine.drug ,ATG5 ,Primary Cell Culture ,Biology ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Exosome ,Cell Line ,lcsh:Biochemistry ,03 medical and health sciences ,Fetus ,medicine ,Autophagy ,Animals ,Humans ,Cisplatin ,Sirolimus ,Adenine ,Research ,Epithelial Cells ,Mesenchymal Stem Cells ,Cell Biology ,Fibroblasts ,Rats ,030104 developmental biology ,Immunology ,Cancer research ,Biomarkers - Abstract
Background The administration of cisplatin is limited due to its nephrotoxic side effects, and prevention of this nephrotoxicity of cisplatin is difficult. Mesenchymal stem cell (MSC)-derived exosomes have been implicated as a novel therapeutic approach for tissue injury. In this study, we demonstrated that the pretreatment of human umbilical cord MSC-derived exosomes (hucMSC-Ex) can prevent the development of cisplatin-induced renal toxicity by activation of autophagy in vitro and in vivo. Methods In vitro, rat renal tubular epithelial (NRK-52E) cells were pre-incubated with exosomes from hucMSC or HFL1 (human lung fibroblast cells; as control) for 30 min, and 3-methyladenine (an autophagic inhibitor) and rapamycin (an autophagic inducer) for 1 h before cisplatin treatment for 8 h, respectively. Cells were harvested for apoptosis assay, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). In vivo, we constructed cisplatin-induced acute kidney injury rat models. Prior to treatment with cisplatin for 0.5 h, hucMSC-Ex or HFL1-Ex were injected into the kidneys via the renal capsule. 3-methyladenine and rapamycin were injected under the kidney capsule before hucMSC-Ex. All animals were sacrificed at 3 days after cisplatin injection. Renal function, Luminex assay, tubular apoptosis and proliferation, and autophagy response were evaluated. Results hucMSC-Ex inhibited cisplatin-induced mitochondrial apoptosis and secretion of inflammatory cytokines in renal tubular epithelial cells in vitro. hucMSC-Ex increased the expression of the autophagic marker protein LC3B and the autophagy-related genes ATG5 and ATG7 in NRK-52E cells. Rapamycin mimicked the effects of hucMSC-Ex in protecting against cisplatin-induced renal injury, while the effects were abrogated by the autophagy inhibitor 3-methyladenine in the animals. Conclusions Our findings indicate that the activation of autophagy induced by hucMSC-Ex can effectively relieve the nephrotoxicity of cisplatin. Therefore, pre-treatment of hucMSC-Ex may be a new method to improve the therapeutic effect of cisplatin. Electronic supplementary material The online version of this article (doi:10.1186/s13287-016-0463-4) contains supplementary material, which is available to authorized users.
- Published
- 2016
38. Exosomes Derived from Akt-Modified Human Umbilical Cord Mesenchymal Stem Cells Improve Cardiac Regeneration and Promote Angiogenesis via Activating Platelet-Derived Growth Factor D
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Jie Ma, Xiaosu Zhao, Wenrong Xu, Li Sun, Xiaoxian Sun, Hui Qian, Wei Zhu, Xiaochun Sun, and Yuanyuan Zhao
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0301 basic medicine ,Angiogenesis ,medicine.medical_treatment ,Neovascularization, Physiologic ,Apoptosis ,Cardioprotection ,Biology ,Exosomes ,Cell Line ,Umbilical Cord ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Translational Research Articles and Reviews ,Cell Movement ,medicine ,Animals ,Humans ,Regeneration ,Receptors, Platelet-Derived Growth Factor ,Protein kinase B ,Cell Proliferation ,Platelet-Derived Growth Factor ,Lymphokines ,Wound Healing ,Growth factor ,Myocardium ,Akt ,Platelet‐derived growth factor D ,Mesenchymal stem cell ,Endothelial Cells ,Heart ,Mesenchymal Stem Cells ,Cell Biology ,General Medicine ,Microvesicles ,Endothelial stem cell ,030104 developmental biology ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,biology.protein ,Stem cell ,Chickens ,Proto-Oncogene Proteins c-akt ,Platelet-derived growth factor receptor ,Developmental Biology ,Tissue‐Specific Progenitor and Stem Cells - Abstract
We have previously demonstrated the cardioprotective effects of exosomes derived from mesenchymal stem cells (MSCs). It is well known that the activation of Akt is involved in stem cell-induced cardioprotection. In the present study, we investigated whether exosomes released from Akt-overexpressing MSCs showed a beneficial effect on cardioprotection and angiogenesis. MSCs were collected from human umbilical cord (hucMSCs), and Akt was transfected into hucMSCs (Akt-hucMSCs) by using an adenovirus transfection system. Exosomes were isolated from control hucMSCs (Exo) and Akt-hucMSCs (Akt-Exo). An acute myocardial infarction model was created by ligation of the left anterior decedent coronary artery (LAD) in rats. Various source exosomes (400 µg of protein) were infused via the tail vein immediately after LAD ligation. The cardiac function was evaluated by using echocardiography after different treatments for 1 and 5 weeks, respectively. Endothelial cell proliferation, migration, and tube-like structure formation, as well as chick allantoic membrane assay, were used to evaluate the angiogenetic effects of Akt-Exo. The results indicated that cardiac function was significantly improved in the animals treated with Akt-Exo. In addition, Akt-Exo significantly accelerated endothelial cell proliferation and migration, tube-like structure formation in vitro, and blood vessel formation in vivo. The expression of platelet-derived growth factor D (PDGF-D) was significantly upregulated in Akt-Exo. However, the angiogenesis was abrogated in endothelial cells treated with the exosomes obtained from MSCs transfected with PDGF-D-siRNA. Our studies suggest that exosomes obtained from Akt-modified hucMSCs are more effective in myocardial infarction therapy through promoting angiogenesis. PDGF-D plays an important role in Akt-Exo-mediated angiogenesis.
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- 2016
39. Exosomes derived from gastric cancer cells activate NF-κB pathway in macrophages to promote cancer progression
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Zhaoji Pan, Lijun Wu, Wenrong Xu, Xu Zhang, Hui Qian, Yaoxiang Sun, Xiao Yuan, Bin Zhang, and Hui Shi
- Subjects
0301 basic medicine ,Exosomes ,Proinflammatory cytokine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Downregulation and upregulation ,Cell Movement ,Stomach Neoplasms ,Cell Line, Tumor ,medicine ,Tumor Microenvironment ,Humans ,Neoplasm Invasiveness ,Cell Proliferation ,Tumor microenvironment ,Cell growth ,Chemistry ,Macrophages ,NF-kappa B ,Cancer ,NF-κB ,General Medicine ,medicine.disease ,Microvesicles ,Cell biology ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer cell ,Disease Progression ,Signal Transduction - Abstract
Exosomes are nano-sized membrane vesicles secreted by both normal and cancer cells. Emerging evidence indicates that cancer cells derived exosomes contribute to cancer progression through the modulation of tumor microenvironment. However, the effects of exosomes derived from gastric cancer cells on macrophages are not well understood. In this study, we investigated the biological role of gastric cancer cells derived exosomes in the activation of macrophages. We demonstrated that gastric cancer cells derived exosomes activated macrophages to express increased levels of proinflammatory factors, which in turn promoted tumor cell proliferation and migration. In addition, gastric cancer cells derived exosomes remarkably upregulated the phosphorylation of NF-κB in macrophages. Inhibiting the activation of NF-κB reversed the upregulation of proinflammatory factors in macrophages and blocked their promoting effects on gastric cancer cells. Moreover, we found that gastric cancer cells derived exosomes could also activate macrophages from human peripheral blood monocytes through the activation of NF-κB. In conclusion, our results suggest that gastric cancer cells derived exosomes stimulate the activation of NF-κB pathway in macrophages to promote cancer progression, which provides a potential therapeutic approach for gastric cancer by interfering with the interaction between exosomes and macrophages in tumor microenvironment.
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- 2016
40. Safety evaluation of exosomes derived from human umbilical cord mesenchymal stromal cell
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Yuanyuan Zhao, Yuping Duan, Xiaoxian Sun, Rongman Xu, Li Sun, Hui Qian, Wenrong Xu, Yiwen Han, and Wei Zhu
- Subjects
0301 basic medicine ,Male ,Cancer Research ,medicine.medical_specialty ,Pathology ,Stromal cell ,Immunology ,Guinea Pigs ,H&E stain ,Myocardial Infarction ,Exosomes ,Mesenchymal Stem Cell Transplantation ,Umbilical cord ,Hemolysis ,Umbilical Cord ,Rats, Sprague-Dawley ,03 medical and health sciences ,In vivo ,Internal medicine ,Immunology and Allergy ,Medicine ,Animals ,Humans ,Genetics (clinical) ,Cells, Cultured ,Transplantation ,Hematology ,business.industry ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Microvesicles ,Rats ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Liver ,Female ,Rabbits ,business - Abstract
Background aims Mounting evidence shows that non–cell-based transplantation of exosomes derived from mesenchymal stromal cells (MSCs) has more potential protective and reparative effects than MSCs have. However, whether it is safe to transplant MSC exosomes into tissues is still not clear. In this study, we evaluated the safety of transplantation of exosomes derived from human umbilical cord MSCs (hucMSC exosomes). Methods hucMSC exosomes were incubated with the cardiac blood from a healthy rabbit, and hemolysis was observed. For analysis of vascular and muscle stimulation, pyrogen, systemic anaphylaxis and hematology indexes, hucMSC exosomes were given to rabbits, guinea pigs and rats. The histological changes in the vascular and muscle sites of injection in rabbits were analyzed by hematoxylin and eosin staining. Allergy symptoms in guinea pigs and rectal temperature of rabbits were observed and recorded. To study safety in vivo , hucMSC exosomes were infused intravenously into rats with acute myocardial infarction. Rats' weight was measured and tail vein blood was collected to evaluate liver and renal function. Results hucMSC exosomes had a protective effect on weight loss and had no adverse effects on liver or renal function. Other detections, such as hemolysis, vascular and muscle stimulation, systemic anaphylaxis, pyrogen and hematology indexes, also showed that hucMSC exosomes were applicable. Conclusions hucMSC exosomes are well tolerated in animal models. This study provides evidence for the safety of intravenous infusion in future clinical therapy.
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- 2015
41. Exosomes derived from human mesenchymal stem cells promote gastric cancer cell growth and migration via the activation of the Akt pathway
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Pengcheng Jiang, Xu Zhang, Wenrong Xu, Hongbing Gu, Hui Qian, Yongchang Chen, Mei Wang, Wei Zhu, and Runbi Ji
- Subjects
0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Epithelial-Mesenchymal Transition ,Cell ,Biology ,Exosomes ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Cancer stem cell ,Cell Movement ,Stomach Neoplasms ,Cell Line, Tumor ,Genetics ,medicine ,Tumor Microenvironment ,Humans ,Epithelial–mesenchymal transition ,Molecular Biology ,PI3K/AKT/mTOR pathway ,Cells, Cultured ,Cell Proliferation ,Tumor microenvironment ,Oncogene ,digestive, oral, and skin physiology ,Mesenchymal stem cell ,Stomach ,Mesenchymal Stem Cells ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Gastric Mucosa ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Molecular Medicine ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Mesenchymal stem cells (MSCs) are a component of the tumor microenvironment and can promote the development of gastric cancer through paracrine mechanism. However, the effects of MSC‑exosomes (MSC‑ex) on gastric cancer are less clear. The present study reported that MSC‑ex promoted the proliferative and metastatic potential of gastric cancer cells ex vivo. It was found that MSC‑ex enhanced the migration and invasion of HGC‑27 cells via the induction of the epithelial‑mesenchymal transition. MSC‑ex increased the expression of mesenchymal markers and reduced the expression of epithelial markers in gastric cancer cells. MSC‑ex also enhanced the tumorigenicity of gastric cancer cells ex vivo. MSC‑ex induced the stemness of gastric cancer cells. The expression of octamer‑binding transcription factor 4, ex determining region Y‑box 2 and Lin28B significantly increased in gastric cancer cells treated with MSC‑ex. The present study further demonstrated that MSC‑ex elicited these biological effects predominantly via the activation of the protein kinase B signaling pathway. Taken together, the present findings provided novel evidence for the role of MSC‑ex in gastric cancer and a new opportunity for improving the efficiency of gastric cancer treatment by targeting MSC‑ex.
- Published
- 2015
42. Exosomes in cancer: small particle, big player
- Author
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Xiao Shuai Yuan, Lijun Wu, Xu Zhang, Wenrong Xu, Hui Qian, and Hui Shi
- Subjects
Target ,Cell signaling ,Cancer Research ,Stromal cell ,Tumor initiation ,Review ,Cell Communication ,Biology ,Exosomes ,Metastasis ,Immune system ,Neoplasms ,medicine ,Biomarkers, Tumor ,Tumor Microenvironment ,Humans ,Molecular Biology ,Cancer ,Tumor microenvironment ,Hematology ,Biomarker ,medicine.disease ,Microvesicles ,Intercellular communication ,Oncology ,Immunology ,Cancer research ,Reprogramming - Abstract
Exosomes have emerged as a novel mode of intercellular communication. Exosomes can shuttle bioactive molecules including proteins, DNA, mRNA, as well as non-coding RNAs from one cell to another, leading to the exchange of genetic information and reprogramming of the recipient cells. Increasing evidence suggests that tumor cells release excessive amount of exosomes, which may influence tumor initiation, growth, progression, metastasis, and drug resistance. In addition, exosomes transfer message from tumor cells to immune cells and stromal cells, contributing to the escape from immune surveillance and the formation of tumor niche. In this review, we highlight the recent advances in the biology of exosomes as cancer communicasomes. We review the multifaceted roles of exosomes, the small secreted particles, in communicating with other cells within tumor microenvironment. Given that exosomes are cell type specific, stable, and accessible from body fluids, exosomes may provide promising biomarkers for cancer diagnosis and represent new targets for cancer therapy.
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- 2015
43. Exosomes derived from human mesenchymal stem cells confer drug resistance in gastric cancer
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Xiao Yuan, Bin Zhang, Wenrong Xu, Runbi Ji, Yongmin Yan, Xu Zhang, Hui Qian, Jianguo Xue, Mei Wang, and Wei Zhu
- Subjects
MAPK/ERK pathway ,Male ,Cell signaling ,Antimetabolites, Antineoplastic ,MAP Kinase Signaling System ,Mice, Nude ,Apoptosis ,Cell Communication ,Biology ,Mitogen-activated protein kinase kinase ,Exosomes ,Mice ,Stomach Neoplasms ,Cell Line, Tumor ,Report ,medicine ,Animals ,Humans ,RNA, Small Interfering ,Extracellular Signal-Regulated MAP Kinases ,Molecular Biology ,Mitogen-Activated Protein Kinase Kinases ,Mice, Inbred BALB C ,Kinase ,Mesenchymal stem cell ,Cancer ,Membrane Transport Proteins ,Mesenchymal Stem Cells ,Cell Biology ,medicine.disease ,Microvesicles ,Cell biology ,Enzyme Activation ,Drug Resistance, Neoplasm ,Cancer cell ,RNA Interference ,raf Kinases ,Fluorouracil ,Guanylate Kinases ,Developmental Biology - Abstract
Mesenchymal stem cells (MSCs) play an important role in chemoresistance. Exosomes have been reported to modify cellular phenotype and function by mediating cell-cell communication. In this study, we aimed to investigate whether exosomes derived from MSCs (MSC-exosomes) are involved in mediating the resistance to chemotherapy in gastric cancer and to explore the underlying molecular mechanism. We found that MSC-exosomes significantly induced the resistance of gastric cancer cells to 5-fluorouracil both in vivo and ex vivo. MSC-exosomes antagonized 5-fluorouracil-induced apoptosis and enhanced the expression of multi-drug resistance associated proteins, including MDR, MRP and LRP. Mechanistically, MSC-exosomes triggered the activation of calcium/calmodulin-dependent protein kinases (CaM-Ks) and Raf/MEK/ERK kinase cascade in gastric cancer cells. Blocking the CaM-Ks/Raf/MEK/ERK pathway inhibited the promoting role of MSC-exosomes in chemoresistance. Collectively, MSC-exosomes could induce drug resistance in gastric cancer cells by activating CaM-Ks/Raf/MEK/ERK pathway. Our findings suggest that MSC-exosomes have profound effects on modifying gastric cancer cells in the development of drug resistance. Targeting the interaction between MSC-exosomes and cancer cells may help improve the efficacy of chemotherapy in gastric cancer.
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- 2015
44. Deregulated microRNAs in gastric cancer tissue-derived mesenchymal stem cells: novel biomarkers and a mechanism for gastric cancer
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Jie Cai, Xiaojun Wu, Hui Qian, Feng Huang, Tingting Yang, Chonghui Zhao, Hui Shi, Q Zhu, Lubin Zhang, Mei Wang, Wenrong Xu, Shui Wang, Bin Zhang, Xu Zhang, and Wenshuai Zhu
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Stromal cell ,Down-Regulation ,Mice, Nude ,Biology ,Exosomes ,Paracrine signalling ,Mice ,Downregulation and upregulation ,Cell Movement ,Stomach Neoplasms ,Cell Line, Tumor ,microRNA ,Paracrine Communication ,medicine ,Biomarkers, Tumor ,Animals ,Humans ,Molecular Diagnostics ,Cell Proliferation ,Mice, Inbred BALB C ,mesenchymal stem cells ,gastric cancer ,Mesenchymal stem cell ,Cancer ,medicine.disease ,Microvesicles ,Up-Regulation ,MicroRNAs ,Oncology ,Lymphatic Metastasis ,Cancer cell ,Cancer research ,cross-talk ,tumour microenvironment - Abstract
Background: MicroRNAs (miRNAs) are involved in gastric cancer development and progression. However, the expression and role of miRNAs in gastric cancer stromal cells are still unclear. Methods: The miRNAs differentially expressed in gastric cancer tissue-derived mesenchymal stem cells (GC-MSCs) relative to adjacent non-cancerous tissue-derived MSCs (GCN-MSCs) and in cancer tissues relative to adjacent non-cancerous tissues were screened using miRNA microarray and validated by quantitative RT–PCR. The impact of GC-MSCs on HGC-27 cells was observed in vitro using colony formation and transwell assays, and these cells were subcutaneously co-injected into mice to assess tumour growth in vivo. Exogenous downregulation of miR-221 expression in cells was achieved using an miRNA inhibitor. Results: miR-214, miR-221 and miR-222 were found to be commonly upregulated in GC-MSCs and cancer tissues. Their levels were tightly associated with lymph node metastasis, venous invasion and the TNM stage. Gastric cancer tissue-derived mesenchymal stem cells significantly promoted HGC-27 growth and migration and increased the expression of miR-221 via paracrine secretion, and the targeted inhibition of miR-221 in GC-MSCs could block its tumour-supporting role. GC-MSC-derived exosomes were found to deliver miR-221 to HGC-27 cells and promoted their proliferation and migration. Conclusions: Gastric cancer tissue-derived mesenchymal stem cells favour gastric cancer progression by transferring exosomal miRNAs to gastric cancer cells, thus providing a novel mechanism for the role of GC-MSCs and new biomarkers for gastric cancer.
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- 2013
45. Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro
- Author
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Wei Zhu, Wenrong Xu, Huitao Xu, Hui Qian, Bingying Wang, Mei Wang, Bin Zhang, Yongmin Yan, Ying Zhou, Hongbing Gu, Huiyi Wu, Fei Mao, Yang Tao, and Shuo Gao
- Subjects
Cellular differentiation ,Proliferation ,Medicine (miscellaneous) ,Apoptosis ,Exosomes ,medicine.disease_cause ,Biochemistry, Genetics and Molecular Biology (miscellaneous) ,Exosome ,Umbilical Cord ,Nephrotoxicity ,medicine ,Animals ,Humans ,Cisplatin ,Chemistry ,Research ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Cell Biology ,Acute kidney injury ,Cell biology ,Oxidative Stress ,Cancer research ,Molecular Medicine ,Female ,Stem cell ,Human umbilical cord mesenchymal stem cells ,Oxidative stress ,medicine.drug - Abstract
Introduction Administration of bone marrow mesenchymal stem cells (MSCs) or secreted microvesicles improves recovery from acute kidney injury (AKI). However, the potential roles and mechanisms are not well understood. In the current study, we focused on the protective effect of exosomes derived from human umbilical cord mesenchymal stem cells (hucMSC-ex) on cisplatin-induced nephrotoxicity in vivo and in vitro. Methods We constructed cisplatin-induced AKI rat models. At 24 h after treatment with cisplatin, hucMSC-ex were injected into the kidneys via the renal capsule; human lung fibroblast (HFL-1)-secreted exosomes (HFL-1-ex) were used as controls. All animals were killed at day 5 after administration of cisplatin. Renal function, histological changes, tubular apoptosis and proliferation, and degree of oxidative stress were evaluated. In vitro, rat renal tubular epithelial (NRK-52E) cells were treated with or without cisplatin and after 6 h treated with or without exosomes. Cells continued to be cultured for 24 h, and were then harvested for western blotting, apoptosis and detection of degree of oxidative stress. Results After administration of cisplatin, there was an increase in blood urea nitrogen (BUN) and creatinine (Cr) levels, apoptosis, necrosis of proximal kidney tubules and formation of abundant tubular protein casts and oxidative stress in rats. Cisplatin-induced AKI rats treated with hucMSC-ex, however, showed a significant reduction in all the above indexes. In vitro, treatment with cisplatin alone in NRK-52E cells resulted in an increase in the number of apoptotic cells, oxidative stress and activation of the p38 mitogen-activated protein kinase (p38MAPK) pathway followed by a rise in the expression of caspase 3, and a decrease in cell multiplication, while those results were reversed in the hucMSCs-ex-treated group. Furthermore, it was observed that hucMSC-ex promoted cell proliferation by activation of the extracellular-signal-regulated kinase (ERK)1/2 pathway. Conclusions The results in the present study indicate that hucMSC-ex can repair cisplatin-induced AKI in rats and NRK-52E cell injury by ameliorating oxidative stress and cell apoptosis, promoting cell proliferation in vivo and in vitro. This suggests that hucMSC-ex could be exploited as a potential therapeutic tool in cisplatin-induced nephrotoxicity.
- Published
- 2013
46. Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo
- Author
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Hui Qian, Yahong Li, Mei Wang, Xiaomeng Xu, Xu Zhang, Wenrong Xu, Jianmei Gu, Yongmin Yan, Wei Zhu, and Ling Huang
- Subjects
Male ,Cancer Research ,Cellular differentiation ,Bone Marrow Cells ,Cell Growth Processes ,Biology ,Exosomes ,Exosome ,chemistry.chemical_compound ,Mice ,In vivo ,Neoplasms ,medicine ,Animals ,Humans ,Mice, Inbred BALB C ,Mesenchymal stem cell ,Cell Differentiation ,Mesenchymal Stem Cells ,Molecular biology ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,Microvesicles ,Vascular endothelial growth factor ,medicine.anatomical_structure ,Oncology ,chemistry ,Tumor progression ,Cancer research ,Bone marrow - Abstract
Mesenchymal stem cells (MSCs) can promote tumor growth in a mouse xenograft model, but the exact mechanism remains unclear. In this study, we investigated the effects of bone marrow MSC-derived exosomes (MSC-exosomes) on tumor growth in vitro and in vivo. Our results showed that MSC-exosomes promoted tumor growth in vivo. MSC-exosomes enhanced vascular endothelial growth factor (VEGF) expression in tumor cells by activating extracellular signal-regulated kinase1/2 (ERK1/2) pathway. Inhibition of ERK1/2 activation reserved the increase of VEGF level by MSC-exosomes. Our findings demonstrate a new mechanism through which MSC-exosome-mediated cell-cell interactions may contribute to tumor progression.
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- 2011
47. Pre-incubation with hucMSC-exosomes prevents cisplatin-induced nephrotoxicity by activating autophagy.
- Author
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Bingying Wang, Haoyuan Jia, Bin Zhang, Juanjuan Wang, Cheng Ji, Xueming Zhu, Yongmin Yan, Lei Yin, Jing Yu, Hui Qian, and Wenrong Xu
- Subjects
EXOSOMES ,CISPLATIN ,NEPHROTOXICOLOGY ,MESENCHYMAL stem cells ,ENZYME-linked immunosorbent assay - Abstract
Background: The administration of cisplatin is limited due to its nephrotoxic side effects, and prevention of this nephrotoxicity of cisplatin is difficult. Mesenchymal stem cell (MSC)-derived exosomes have been implicated as a novel therapeutic approach for tissue injury. In this study, we demonstrated that the pretreatment of human umbilical cord MSC-derived exosomes (hucMSC-Ex) can prevent the development of cisplatin-induced renal toxicity by activation of autophagy in vitro and in vivo. Methods: In vitro, rat renal tubular epithelial (NRK-52E) cells were pre-incubated with exosomes from hucMSC or HFL1 (human lung fibroblast cells; as control) for 30 min, and 3-methyladenine (an autophagic inhibitor) and rapamycin (an autophagic inducer) for 1 h before cisplatin treatment for 8 h, respectively. Cells were harvested for apoptosis assay, enzyme-linked immunosorbent assay (ELISA), Western blot, and quantitative real-time polymerase chain reaction (qRT-PCR). In vivo, we constructed cisplatin-induced acute kidney injury rat models. Prior to treatment with cisplatin for 0.5 h, hucMSC-Ex or HFL1-Ex were injected into the kidneys via the renal capsule. 3-methyladenine and rapamycin were injected under the kidney capsule before hucMSC-Ex. All animals were sacrificed at 3 days after cisplatin injection. Renal function, Luminex assay, tubular apoptosis and proliferation, and autophagy response were evaluated. Results: hucMSC-Ex inhibited cisplatin-induced mitochondrial apoptosis and secretion of inflammatory cytokines in renal tubular epithelial cells in vitro. hucMSC-Ex increased the expression of the autophagic marker protein LC3B and the autophagy-related genes ATG5 and ATG7 in NRK-52E cells. Rapamycin mimicked the effects of hucMSC-Ex in protecting against cisplatin-induced renal injury, while the effects were abrogated by the autophagy inhibitor 3-methyladenine in the animals. Conclusions: Our findings indicate that the activation of autophagy induced by hucMSC-Ex can effectively relieve the nephrotoxicity of cisplatin. Therefore, pre-treatment of hucMSC-Ex may be a new method to improve the therapeutic effect of cisplatin. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
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48. Exosomes derived from human mesenchymal stem cells promote gastric cancer cell growth and migration via the activation of the Akt pathway.
- Author
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HONGBING GU, RUNBI JI, XU ZHANG2, MEI WANG, WEI ZHU, HUI QIAN, YONGCHANG CHEN, PENGCHENG JIANG, and WENRONG XU
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EXOSOMES ,PARACRINE mechanisms ,CANCER cell growth ,MESENCHYMAL stem cells ,THERAPEUTICS - Abstract
Mesenchymal stem cells (MSCs) are a component of the tumor microenvironment and can promote the development of gastric cancer through paracrine mechanism. However, the effects of MSC-exosomes (MSC-ex) on gastric cancer are less clear. The present study reported that MSC-ex promoted the proliferative and metastatic potential of gastric cancer cells ex vivo. It was found that MSC-ex enhanced the migration and invasion of HGC-27 cells via the induction of the epithelial-mesenchymal transition. MSC-ex increased the expression of mesenchymal markers and reduced the expression of epithelial markers in gastric cancer cells. MSC-ex also enhanced the tumorigenicity of gastric cancer cells ex vivo. MSC-ex induced the stemness of gastric cancer cells. The expression of octamer-binding transcription factor 4, ex determining region Y-box 2 and Lin28B significantly increased in gastric cancer cells treated with MSC-ex. The present study further demonstrated that MSC-ex elicited these biological effects predominantly via the activation of the protein kinase B signaling pathway. Taken together, the present findings provided novel evidence for the role of MSC-ex in gastric cancer and a new opportunity for improving the efficiency of gastric cancer treatment by targeting MSC-ex. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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49. Gastric Cancer Exosomes Trigger Differentiation of Umbilical Cord Derived Mesenchymal Stem Cells to Carcinoma-Associated Fibroblasts through TGF-β/Smad Pathway
- Author
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Wei Zhu, Fei Mao, Xu Zhang, Jianmei Gu, Yunyan Shi, Ling Huang, Chonghui Zhao, Li Shen, Yongmin Yan, Hui Qian, and Wenrong Xu
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Cellular differentiation ,lcsh:Medicine ,Smad2 Protein ,SMAD ,Signal transduction ,Exosomes ,p38 Mitogen-Activated Protein Kinases ,Umbilical Cord ,Molecular cell biology ,Cell Movement ,Transforming Growth Factor beta ,Basic Cancer Research ,lcsh:Science ,Multidisciplinary ,Stem Cells ,Signaling cascades ,Cell Differentiation ,Signaling in Selected Disciplines ,Endocytosis ,Cell biology ,Oncology ,Medicine ,Cellular Types ,Research Article ,Biology ,Stomach Neoplasms ,Cell Line, Tumor ,Gastrointestinal Tumors ,Biomarkers, Tumor ,medicine ,Humans ,Smad3 Protein ,Oncogenic Signaling ,Tumor microenvironment ,lcsh:R ,Mesenchymal stem cell ,Cancers and Neoplasms ,Cancer ,Mesenchymal Stem Cells ,Fibroblasts ,medicine.disease ,Microvesicles ,Enzyme Activation ,Gastric Cancer ,TGF-beta signaling cascade ,Cancer cell ,lcsh:Q ,Developmental Biology ,Transforming growth factor - Abstract
Background Mesenchymal stem cells (MSCs) promote tumor growth by differentiating into carcinoma-associated fibroblasts (CAFs) and composing the tumor microenvironment. However, the mechanisms responsible for the transition of MSCs to CAFs are not well understood. Exosomes regulate cellular activities by mediating cell-cell communication. In this study, we aimed to investigate whether cancer cell-derived exosomes were involved in regulating the differentiation of human umbilical cord-derived MSCs (hucMSCs) to CAFs. Methodology/Principal Findings We first showed that gastric cancer cell-derived exosomes induced the expression of CAF markers in hucMSCs. We then demonstrated that gastric cancer cell-derived exosomes stimulated the phosphorylation of Smad-2 in hucMSCs. We further confirmed that TGF-β receptor 1 kinase inhibitor attenuated Smad-2 phosphorylation and CAF marker expression in hucMSCs after exposure to gastric cancer cell-derived exosomes. Conclusion/Significance Our results suggest that gastric cancer cells triggered the differentiation of hucMSCs to CAFs by exosomes-mediated TGF-β transfer and TGF-β/Smad pathway activation, which may represent a novel mechanism for MSCs to CAFs transition in cancer.
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- 2012
50. Exosomes in cancer: small particle, big player.
- Author
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Xu Zhang, Xiao Yuan, Hui Shi, Lijun Wu, Hui Qian, and Wenrong Xu
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EXOSOMES ,CELL communication ,MESSENGER RNA ,CANCER cells ,STROMAL cells ,CANCER treatment - Abstract
Exosomes have emerged as a novel mode of intercellular communication. Exosomes can shuttle bioactive molecules including proteins, DNA, mRNA, as well as non-coding RNAs from one cell to another, leading to the exchange of genetic information and reprogramming of the recipient cells. Increasing evidence suggests that tumor cells release excessive amount of exosomes, which may influence tumor initiation, growth, progression, metastasis, and drug resistance. In addition, exosomes transfer message from tumor cells to immune cells and stromal cells, contributing to the escape from immune surveillance and the formation of tumor niche. In this review, we highlight the recent advances in the biology of exosomes as cancer communicasomes. We review the multifaceted roles of exosomes, the small secreted particles, in communicating with other cells within tumor microenvironment. Given that exosomes are cell type specific, stable, and accessible from body fluids, exosomes may provide promising biomarkers for cancer diagnosis and represent new targets for cancer therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
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