过表达microRNA-34a的人骨髓间充质干细胞分泌外泌体通过下调MYCN改善胶质母细胞瘤的发展。

IF 6.6 2区 医学 Q1 Medicine Cellular Oncology Pub Date : 2019-12-01 Epub Date: 2019-07-22 DOI:10.1007/s13402-019-00461-z
Bin Wang, Zhong-Hua Wu, Ping-Yang Lou, Chang Chai, Shuang-Yin Han, Jian-Fang Ning, Ming Li
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引用次数: 26

摘要

目的:外泌体通过影响肿瘤微环境调节和肿瘤增殖的信号通路在细胞间通讯中发挥重要作用,包括在胶质母细胞瘤(GBM)中。然而,迄今为止,关于人骨髓间充质干细胞(hBMSC)来源的外泌体对GBM发育的抑制作用的研究还很有限。因此,我们开始评估hBMSC分泌外泌体,特别是那些携带microRNA-34a (miR-34a)的外泌体在GBM发展中的作用。方法:采用微阵列表达分析鉴定差异表达基因,预测调节MYCN表达的mirna。接下来,用miR-34a模拟物或抑制剂转染hBMSCs,然后分离外泌体。体外检测外泌体暴露的GBM细胞(T-98G、LN229和A-172)的增殖、凋亡、迁移、侵袭及替莫唑胺(TMZ)的化学敏感性。利用慢病毒转染研究了MYCN调控的机制。通过皮下注射miR34a含量上调的hBMSCs,在移植GBM细胞的裸鼠中测量了外泌体miR-34a的体内抑制作用。结果:我们发现低表达的miR-34a特异性靶向并负向调节GBM细胞中MYCN的表达。此外,我们发现miR-34a通过hbmsc衍生的外泌体递送到T-98G、LN229和A-172 GBM细胞。在hbmsc来源的外泌体中外源性过表达miR-34a导致GBM细胞体外和体内增殖、侵袭、迁移和肿瘤发生受到抑制,同时通过沉默MYCN促进GBM细胞对TMZ的化学敏感性。结论:根据我们的数据,我们得出结论,hbmsc衍生的过表达miR-34a的外泌体可能有助于GBM的治疗靶向和临床管理。
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Human bone marrow-derived mesenchymal stem cell-secreted exosomes overexpressing microRNA-34a ameliorate glioblastoma development via down-regulating MYCN.

Purpose: Exosomes play important roles in intercellular communication through signaling pathways affecting tumor microenvironment modulation and tumor proliferation, including those in glioblastoma (GBM). As yet, however, limited studies have been conducted on the inhibitory effect of human bone marrow-derived mesenchymal stem cell (hBMSC)-derived exosomes on GBM development. Therefore, we set out to assess the role of hBMSC secreted exosomes, in particular those carrying microRNA-34a (miR-34a), in the development of GBM.

Methods: Microarray-based expression analysis was employed to identify differentially expressed genes and to predict miRNAs regulating MYCN expression. Next, hBMSCs were transfected with a miR-34a mimic or inhibitor after which exosomes were isolated. Proliferation, apoptosis, migration, invasion and temozolomide (TMZ) chemosensitivity of exosome-exposed GBM cells (T-98G, LN229 and A-172) were measured in vitro. The mechanism underlying MYCN regulation was investigated using lentiviral transfections. The in vivo inhibitory effect of exosomal miR-34a was measured in nude mice xenografted with GBM cells through subcutaneous injection of hBMSCs with an upregulated miR34a content.

Results: We found that poorly-expressed miR-34a specifically targeted and negatively regulated the expression of MYCN in GBM cells. In addition we found that miR-34a was delivered to T-98G, LN229 and A-172 GBM cells via hBMSC-derived exosomes. Exogenous overexpression of miR-34a in hBMSC-derived exosomes resulted in inhibition of GBM cell proliferation, invasion, migration and tumorigenesis in vitro and in vivo, while promoting the chemosensitivity of GBM cells to TMZ by silencing MYCN.

Conclusions: From our data we conclude that hBMSC-derived exosomes overexpressing miR-34a may be instrumental for the therapeutic targeting and clinical management of GBM.

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来源期刊
Cellular Oncology
Cellular Oncology Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
10.40
自引率
1.50%
发文量
0
审稿时长
16 weeks
期刊介绍: The Official Journal of the International Society for Cellular Oncology Focuses on translational research Addresses the conversion of cell biology to clinical applications Cellular Oncology publishes scientific contributions from various biomedical and clinical disciplines involved in basic and translational cancer research on the cell and tissue level, technical and bioinformatics developments in this area, and clinical applications. This includes a variety of fields like genome technology, micro-arrays and other high-throughput techniques, genomic instability, SNP, DNA methylation, signaling pathways, DNA organization, (sub)microscopic imaging, proteomics, bioinformatics, functional effects of genomics, drug design and development, molecular diagnostics and targeted cancer therapies, genotype-phenotype interactions. A major goal is to translate the latest developments in these fields from the research laboratory into routine patient management. To this end Cellular Oncology forms a platform of scientific information exchange between molecular biologists and geneticists, technical developers, pathologists, (medical) oncologists and other clinicians involved in the management of cancer patients. In vitro studies are preferentially supported by validations in tumor tissue with clinicopathological associations.
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