Exosomal miR-21-5p derived from gastric cancer promotes peritoneal metastasis via mesothelial-to-mesenchymal transition.
Exosomal miR-21-5p derived from gastric cancer promotes peritoneal metastasis via mesothelial-to-mesenchymal transition.
复制标题
DOI：
10.1038/s41419-018-0928-8
复制
发表时间：
2018-08-28
影响因子：
9
通讯作者：
Xu Z
中科院分区：
文献类型：
--
作者：
Li Q;Li B;Li Q;Wei S;He Z;Huang X;Wang L;Xia Y;Xu Z;Li Z;Wang W;Yang L;Zhang D;Xu Z
腹膜转移是胃癌的主要转移途径，其机制尚不清楚。腹膜间皮细胞（PMC）经历间皮间质转化（MMT），为转移性癌细胞提供有利的环境。在本研究中，我们研究了外泌体 miR-21-5p 如何诱导 MMT 并促进腹膜转移。通过透射电子显微镜和蛋白质印迹分析鉴定胃癌（GC）来源的外泌体，然后通过 PKH-67 染色证实外泌体的摄取。通过实时定量聚合酶链反应（qRT-PCR）和蛋白质印迹测量miR-21-5p和SMAD7的表达，并通过荧光素酶报告基因测定证实miR-21-5p与其靶基因SMAD7之间的相互作用。通过侵袭测定、粘附测定、免疫荧光测定和蛋白质印迹测定PMC的MMT。同时，建立小鼠肿瘤腹膜播散模型，探讨外泌体miR-21-5p在体内腹膜转移中的作用。我们发现 PMC 可以内化 GC 衍生的外泌体 miR-21-5p，并导致 PMC 中 miR-21-5p 水平增加。通过各种类型的体外和体内实验，我们证实外泌体miR-21-5p能够诱导PMCs的MMT并促进肿瘤腹膜转移。此外，我们的研究表明，外泌体 miR-21-5p 通过靶向 SMAD7 激活 TGF-β/Smad 通路来促进这一过程。总而言之，我们的数据表明外泌体 miR-21-5p 诱导 PMC 的 MMT 并通过靶向 SMAD7 促进癌症腹膜传播。外泌体miR-21-5p可能是GC腹膜转移的新治疗靶点。
Peritoneal metastasis is a primary metastatic route for gastric cancers, and the mechanisms underlying this process are still unclear. Peritoneal mesothelial cells (PMCs) undergo mesothelial-to-mesenchymal transition (MMT) to provide a favorable environment for metastatic cancer cells. In this study, we investigated how the exosomal miR-21-5p induces MMT and promotes peritoneal metastasis. Gastric cancer (GC)-derived exosomes were identified by transmission electron microscopy and western blot analysis, then the uptake of exosomes was confirmed by PKH-67 staining. The expression of miR-21-5p and SMAD7 were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, and the interactions between miR-21-5p and its target genes SMAD7 were confirmed by Luciferase reporter assays. The MMT of PMCs was determined by invasion assays, adhesion assays, immunofluorescent assay, and western blot. Meanwhile, mouse model of tumor peritoneal dissemination model was performed to investigate the role of exosomal miR-21-5p in peritoneal metastasis in vivo. We found that PMCs could internalize GC-derived exosomal miR-21-5p and led to increased levels of miR-21-5p in PMCs. Through various types of in vitro and in vivo assays, we confirmed that exosomal miR-21-5p was able to induce MMT of PMCs and promote tumor peritoneal metastasis. Moreover, our study revealed that this process was promoted by exosomal miR-21-5p through activating TGF-β/Smad pathway via targeting SMAD7. Altogether, our data suggest that exosomal miR-21-5p induces MMT of PMCs and promote cancer peritoneal dissemination by targeting SMAD7. The exosomal miR-21-5p may be a novel therapeutic target for GC peritoneal metastasis.
登录
查看更多内容
影响因子：
19.6
作者：
Rougier, JP;Moullier, P;Ronco, PM
通讯作者：
Ronco, PM
影响因子：
51.1
作者：
Herrero, Rolando;Gonzalez, Paula;Markowitz, Lauri E.
通讯作者：
Markowitz, Lauri E.
影响因子：
50.3
作者：
Becker A;Thakur BK;Weiss JM;Kim HS;Peinado H;Lyden D
通讯作者：
Lyden D
影响因子：
14.9
作者：
Mathivanan S;Fahner CJ;Reid GE;Simpson RJ
通讯作者：
Simpson RJ
影响因子：
11.2
作者：
Gastpar, R;Gehrmann, M;Multhoff, G
通讯作者：
Multhoff, G