piRNA-823 delivered by multiple myeloma-derived extracellular vesicles promoted tumorigenesis through re-educating endothelial cells in the tumor environment
piRNA-823 delivered by multiple myeloma-derived extracellular vesicles promoted tumorigenesis through re-educating endothelial cells in the tumor environment
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由多发性骨髓瘤来源的细胞外囊泡递送的 piRNA-823 通过在肿瘤环境中重新教育内皮细胞来促进肿瘤发生。
DOI：
10.1038/s41388-019-0788-4
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发表时间：
2019-06-27
期刊：
影响因子：
8
通讯作者：
Wu, Qiuling
中科院分区：
文献类型：
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作者：
Li, Beibei;Hong, Jiaxin;Wu, Qiuling
细胞外囊泡（EV）可以在肿瘤微环境中携带广泛的RNA，并且对于肿瘤与周围基质细胞（包括内皮细胞）之间的通信至关重要。Piwi相互作用RNA（piRNA）是参与多发性骨髓瘤（MM）发病机制的重要调节因子。然而，关于皮尔纳-823在MM和内皮细胞之间的细胞间通讯中的作用知之甚少。在这项研究中，我们发现皮尔纳-823主要积累在来自MM患者外周血的EV和来自MM细胞的EV（MM-衍生的EV）中。增加的皮尔纳-823表达与MM的晚期和不良预后相关。MM衍生的EV有效地将皮尔纳-823转移到EA.hy926内皮细胞。设计皮尔纳-823模拟物和抑制剂以上调或抑制皮尔纳-823的内源性功能。用皮尔纳-823模拟物转染或用MM衍生的EV处理通过增强VEGF、IL-6和ICAM-1的表达并减弱凋亡来显著促进EA.hy926细胞的增殖、管形成和侵袭。用皮尔纳-823模拟物转染或用MM衍生的EV预处理的EA.hy926细胞促进小鼠中异种移植物MM的生长。相比之下，用皮尔纳-823抑制剂转染或用来自皮尔纳-823抑制剂转染的MM细胞的EV处理具有完全相反的效果。我们的研究结果表明，MM衍生的EV携带的皮尔纳-823对于通过改变其生物学特性将EC再教育到适合MM细胞生长的独特环境至关重要。我们的研究结果可能为开发新的piRNA介导的MM预后分层和治疗策略铺平道路。
Extracellular vesicles (EVs) can carry a wide array of RNAs in the tumor microenvironment, and are crucial for communication between tumor and surrounding stromal cells, including endothelial cells. Piwi-interacting RNAs (piRNAs) are important regulators implicated in the pathogenesis of multiple myeloma (MM). However, little is understood about the role of piRNA-823 in intercellular communication between MM and endothelial cells. In this study, we found that piRNA-823 mainly accumulated in EVs from peripheral blood of MM patients and EVs derived from MM cells (MM-derived-EVs). Increased piRNA-823 expression was associated with late stages and poor prognosis of MM. The MM-derived-EVs effectively transferred piRNA-823 to EA.hy926 endothelial cells. The piRNA-823 mimic and inhibitor were designed to upregulate or to suppress the endogenous function of piRNA-823. Transfection with piRNA-823 mimic or treatment with MM-derived-EVs significantly promoted the proliferation, tube formation, and invasion of EA.hy926 cells by enhancing the expression of VEGF, IL-6, and ICAM-1 and attenuating apoptosis. EA.hy926 cells transfected with piRNA-823 mimic or pre-treated with MM-derived-EVs promoted the growth of xenograft MM in mice. In contrast, the transfection with piRNA-823 inhibitor or treatment with EVs from piRNA-823 inhibitor-transfected-MM cells had diametrically opposite effects. Our findings demonstrated that piRNA-823 carried by MM-derived-EVs is essential for the re-education of ECs toward a unique environment amenable to the growth of MM cells by altering its biological characteristics. Our findings may pave the way for the development of new piRNA-mediated prognostic stratification and therapeutic strategies for MM.