Vps4A functions as a tumor suppressor by regulating the secretion and uptake of exosomal microRNAs in human hepatoma cells.
Vps4A functions as a tumor suppressor by regulating the secretion and uptake of exosomal microRNAs in human hepatoma cells.
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Vps4A 通过调节人肝癌细胞中外泌体 MicroRNA 的分泌和摄取发挥肿瘤抑制作用
DOI：
10.1002/hep.27660
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发表时间：
2015-04
期刊：
影响因子：
--
通讯作者：
Min J
中科院分区：
文献类型：
--
作者：
Wei JX;Lv LH;Wan YL;Cao Y;Li GL;Lin HM;Zhou R;Shang CZ;Cao J;He H;Han QF;Liu PQ;Zhou G;Min J
MicroRNAs(MiRNAs)的去调控在人类肝癌的发生中起着重要作用。在这项研究中，我们强调外切体是参与调节肝细胞癌(HCC)细胞miRNA谱的媒介。首先，我们研究了不同的miRNA在肝癌细胞和肝癌细胞来源的外体中的表达谱。其次，共培养实验表明，肝癌细胞来源的外切体促进了肝癌细胞的生长、迁移和侵袭，并具有将miRNAs运送到受体细胞的能力。此外，我们的数据显示，Vps4A，一个外切体生物发生的关键调节因子，在肝细胞癌组织中经常下调。肝细胞癌组织中Vps4A的表达降低与肿瘤的进展和转移有关。体外研究表明，Vps4A抑制肝癌细胞的生长、集落形成、迁移和侵袭。我们进一步研究了Vps4A在抑制外切体生物活性中的作用和参与，并表征了它削弱细胞对外切体的反应的能力。通过小RNA测序，我们证明了Vps4A促进了致癌miRNAs在外体中的分泌，并促进了抑癌基因miRNAs在细胞中的积累和摄取。鉴定了Vps4A相关miRNAs的一个子集。京都百科全书的基因和基因组途径分析表明，磷脂酰肌醇-3-激酶/Akt信号通路是这些miRNAs最可能的调控途径。事实上，我们证明了Vps4A过表达使磷脂酰肌醇-3-激酶/Akt途径失活。Exosome介导的miRNA转移是肝癌细胞miRNA表达谱自我调节的重要机制，而Vps4A可能作为一种肿瘤抑制因子，利用exosome作为介体调节肝癌细胞miRNAs的分泌和摄取，为研究肝癌的发生发展提供了新的思路。
The deregulation of microRNAs (miRNAs) plays an important role in human hepatocarcinogenesis. In this study, we highlight exosomes as mediators involved in modulating miRNA profiles in hepatocellular carcinoma (HCC) cells. First, we examined the different miRNA expression profiles in HCC cells and HCC cell–derived exosomes. Next, coculture experiments indicated that HCC cell–derived exosomes promoted the cell growth, migration, and invasion of HCC cells and had the ability to shuttle miRNAs to recipient cells. Further, our data showed that Vps4A, a key regulator of exosome biogenesis, was frequently down-regulated in HCC tissues. The reduction of Vps4A in HCC tissues was associated with tumor progression and metastasis. In vitro studies revealed that Vps4A repressed the growth, colony formation, migration, and invasion of HCC cells. We further investigated the role and involvement of Vps4A in suppressing the bioactivity of exosomes and characterized its ability to weaken the cell response to exosomes. By small RNA sequencing, we demonstrated that Vps4A facilitated the secretion of oncogenic miRNAs in exosomes as well as accumulation and uptake of tumor suppressor miRNAs in cells. A subset of Vps4A-associated miRNAs was identified. Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that the phosphatidylinositol-3-kinase/Akt signaling pathway was the most likely candidate pathway for modulation by these miRNAs. Indeed, we proved that the phosphatidylinositol-3-kinase/Akt pathway was inactivated by Vps4A overexpression. Exosome-mediated miRNA transfer is an important mechanism of self-modulation of the miRNA expression profiles in HCC cells, and Vps4A may function as a tumor suppressor, which utilizes exosomes as mediators to regulate the secretion and uptake of miRNAs in hepatoma cells; these observations provide new insights into the development of HCC.