C6-神经酰胺处理通过miR-29b/Akt途径抑制多发性骨髓瘤外泌体的促血管生成活性。
C6-ceramide treatment inhibits the proangiogenic activity of multiple myeloma exosomes via the miR-29b/Akt pathway.
作者信息
Liu Liping, Ye Qinmao, Liu Langni, Bihl Ji Chen, Chen Yanfang, Liu Jing, Cheng Qian
机构信息
Department of General Surgery, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
Department of Physiology and Cell Biology, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
出版信息
J Transl Med. 2020 Aug 3;18(1):298. doi: 10.1186/s12967-020-02468-9.
BACKGROUND
The increased bone marrow angiogenesis is involved in the progression of multiple myeloma (MM) with the underlying mechanism poorly understood. Cancer-released exosomes could play an important role in the pathological angiogenesis through exosomal microRNAs (miRs) delivery. It is reported that miR-29b played an important role in regulating the tumor angiogenesis.
METHODS
In this study, we explored the role of C6-ceramide (C6-cer, a Ceramide pathway activator) in the angiogenic effect of MM exosomes and its potential mechanism. MM cells (OPM2 and RPMI-8226) treated with C6-cer were studied for its effects on the endothelial cell (EC) functions.
RESULTS
Our results showed that exosomes released from MM cells treated by C6-cer (Exo) significantly inhibited the proliferation, migration and tube formation of ECs. For mechanism studies, we found that the level of miR-29b was increased in ECs treated by Exo, while mRNA and protein expressions of Akt3, PI3K and VEGFA were decreased in ECs, indicating the involvement of Akt pathway. Furthermore, downregulation of miR-29b by inhibitor administration could prevent the Exo-induced cell proliferation, migration and angiogenesis of ECs, accompanied with the increased expressions of Akt3, PI3K and VEGFA.
CONCLUSIONS
Collectively, our data suggest that Exo-mediated miR-29b expression participates in the progression of MM through suppressing the proliferation, migration and angiogenesis of ECs by targeting Akt signal pathway.
背景
骨髓血管生成增加参与了多发性骨髓瘤（MM）的进展，但其潜在机制尚不清楚。癌症释放的外泌体可通过外泌体微小RNA（miR）传递在病理性血管生成中发挥重要作用。据报道，miR-29b在调节肿瘤血管生成中起重要作用。
方法
在本研究中，我们探讨了C6-神经酰胺（C6-cer，一种神经酰胺途径激活剂）在MM外泌体血管生成作用中的作用及其潜在机制。研究了用C6-cer处理的MM细胞（OPM2和RPMI-8226）对内皮细胞（EC）功能的影响。
结果
我们的结果表明，C6-cer处理的MM细胞释放的外泌体（Exo）显著抑制了ECs的增殖、迁移和管形成。在机制研究中，我们发现Exo处理的ECs中miR-29b水平升高，而ECs中Akt3、PI3K和VEGFA的mRNA和蛋白表达降低，表明Akt途径参与其中。此外，通过给予抑制剂下调miR-29b可以阻止Exo诱导的ECs细胞增殖、迁移和血管生成，同时伴随着Akt3、PI3K和VEGFA表达的增加。
结论
总体而言，我们的数据表明，Exo介导的miR-29b表达通过靶向Akt信号通路抑制ECs的增殖、迁移和血管生成，参与了MM的进展。
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