C6-ceramide treatment inhibits the proangiogenic activity of multiple myeloma exosomes via the miR-29b/Akt pathway
C6-ceramide treatment inhibits the proangiogenic activity of multiple myeloma exosomes via the miR-29b/Akt pathway
复制标题
C6-神经酰胺治疗通过 miR-29b/Akt 途径抑制多发性骨髓瘤外泌体的促血管生成活性
DOI：
10.1186/s12967-020-02468-9
复制
发表时间：
2020-08-03
影响因子：
7.4
通讯作者：
Cheng, Qian
中科院分区：
文献类型：
--
作者：
Liu, Liping;Ye, Qinmao;Cheng, Qian
背景骨髓血管生成增加参与多发性骨髓瘤（MM）的进展，其机制尚不清楚。癌细胞释放的exosomal microRNAs（miRs）可在病理性血管生成中发挥重要作用。方法本研究探讨C6-cer（C6-ceramide，Ceramide pathway activator）在MM exosomes促血管生成中的作用及其可能机制。用C6-cer处理MM细胞（OPM 2和RPMI-8226），观察其对内皮细胞（EC）功能的影响。结果C6-cer处理MM细胞后，释放的exosomes（ExoC 6-cer）明显抑制EC的增殖、迁移和管腔形成。ExoC 6-cer诱导的内皮细胞miR-29 b表达增加，Akt 3、PI 3 K和VEGFA的mRNA和蛋白表达降低，提示Akt通路参与了ExoC 6-cer诱导的内皮细胞凋亡。此外，通过抑制剂给药下调miR-29 b可抑制ExoC 6-cer诱导的EC增殖、迁移和血管生成，并伴随Akt 3、PI 3 K和VEGFA表达的增加。通过靶向Akt信号通路来抑制内皮细胞的迁移和血管生成。
BackgroundThe 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.MethodsIn 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.ResultsOur results showed that exosomes released from MM cells treated by C6-cer (ExoC6-cer) 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 ExoC6-cer, 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 ExoC6-cer-induced cell proliferation, migration and angiogenesis of ECs, accompanied with the increased expressions of Akt3, PI3K and VEGFA.ConclusionsCollectively, our data suggest that ExoC6-cer-mediated miR-29b expression participates in the progression of MM through suppressing the proliferation, migration and angiogenesis of ECs by targeting Akt signal pathway.