Gastric cancer-derived exosomal miR-519a-3p promotes liver metastasis by inducing intrahepatic M2-like macrophage-mediated angiogenesis.
Gastric cancer-derived exosomal miR-519a-3p promotes liver metastasis by inducing intrahepatic M2-like macrophage-mediated angiogenesis.
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胃癌来源的外泌体 miR-519a-3p 通过诱导肝内 M2 样巨噬细胞介导的血管生成促进肝转移
DOI：
10.1186/s13046-022-02499-8
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发表时间：
2022-10-10
影响因子：
11.3
通讯作者：
Xu, Zekuan
中科院分区：
文献类型：
--
作者：
Qiu, Shengkui;Xie, Li;Lu, Chen;Gu, Chao;Xia, Yiwen;Lv, Jialun;Xuan, Zhe;Fang, Lang;Yang, Jing;Zhang, Lu;Li, Zheng;Wang, Weizhi;Xu, Hao;Li, Bowen;Xu, Zekuan
肝转移是影响胃癌患者预后的主要因素，但胃癌肝转移的分子机制尚不清楚。外泌体已被确定为肿瘤细胞和微环境之间通信的重要介质。因此，我们试图研究原代GC细胞对肝脏微环境的影响以及外泌体microRNA（exo-miRNA）在GC-LM中的作用。使用顺序差速离心、透射电子显微镜和NanoSight分析来提取和表征外泌体。使用GC衍生的外泌体中的MicroRNA测序和PMA处理的THP-1细胞中的mRNA测序分别鉴定外泌体中差异表达的miRNA和巨噬细胞中外泌体miR-519 a-3 p（exo-miR-519 a-3 p）的功能靶标。通过免疫荧光观察外泌体的示踪和内化以及exo-miR-519 a-3 p的转移。使用小管形成测定、主动脉环测定和外泌体训练的GC-LM模型来研究GC衍生的外泌体和exo-miR-519 a-3 p在血管生成和GC-LM中的作用。采用荧光素酶报告基因分析、qRT-PCR、Western blot、ELISA、流式细胞术和免疫荧光等方法研究exo-miR-519 a-3 p在GC-LM中的调控机制。GC-LM患者血清外泌体中miR-519 a-3 p的表达水平显著高于非LM患者，且exo-miR-519 a-3 p的高表达表明预后较差。GC衍生的外泌体主要积聚在肝脏中并被肝内巨噬细胞内化。在机制上，exo-miR-519 a-3 p通过靶向DUSP 2激活MAPK/ERK途径，从而引起巨噬细胞的M2样极化。M2样极化巨噬细胞通过诱导血管生成和促进肝内转移前小生境形成来加速GC-LM。我们的研究结果表明，exo-miR-519 a-3 p在介导原代GC细胞和肝内巨噬细胞之间的串扰中起关键作用，并且是GC-LM的潜在治疗靶点。在线版本包含补充材料，可通过10.1186/s13046-022-02499-8获得。
Liver metastasis (LM) is a major obstacle to the prognosis of gastric cancer (GC) patients, but the molecular mechanism underlying gastric cancer liver metastasis (GC-LM) remains unknown. Exosomes have been identified as an important mediator of communication between tumor cells and the microenvironment. Therefore, we sought to investigate the effects of primary GC cells on the liver microenvironment and the role of exosomal microRNAs (exo-miRNA) in GC-LM. Sequential differential centrifugation, transmission electron microscopy and NanoSight analysis were used to extract and characterize exosomes. MicroRNA sequencing in GC-derived exosomes and mRNA sequencing in PMA-treated THP-1 cells were used to identify differentially expressed miRNAs in exosomes and the functional targets of exosomal miR-519a-3p (exo-miR-519a-3p) in macrophages, respectively. Tracing and internalization of exosomes and transfer of exo-miR-519a-3p were observed by immunofluorescence. Tubule formation assays, aortic ring assays, and exosome-educated GC-LM model were used to investigate the roles of GC-derived exosomes and exo-miR-519a-3p in angiogenesis and GC-LM. Luciferase reporter assay, qRT-PCR, Western blot, ELISA, flow cytometry and immunofluorescence were used to investigate the regulatory mechanism of exo-miR-519a-3p at GC-LM. The expression level of miR-519a-3p in serum exosomes was significantly higher in GC-LM patients than in patients without LM, and high expression of exo-miR-519a-3p indicates a worse prognosis. GC-derived exosomes are mainly accumulated in the liver and internalized by intrahepatic macrophages. Mechanistically, exo-miR-519a-3p activates the MAPK/ERK pathway by targeting DUSP2, thereby causing M2-like polarization of macrophages. M2-like polarized macrophages accelerate GC-LM by inducing angiogenesis and promoting intrahepatic premetastatic niche formation. Our results indicate that exo-miR-519a-3p plays a critical role in mediating crosstalk between primary GC cells and intrahepatic macrophages and is a potential therapeutic target for GC-LM. The online version contains supplementary material available at 10.1186/s13046-022-02499-8.
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影响因子：
10.9
作者：
Baumann D;Drebant J;Hägele T;Burger L;Serger C;Lauenstein C;Dudys P;Erdmann G;Offringa R
通讯作者：
Offringa R
影响因子：
64.8
作者：
Headley MB;Bins A;Nip A;Roberts EW;Looney MR;Gerard A;Krummel MF
通讯作者：
Krummel MF
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D
miR-519a通过靶向STAT3/Bcl2信号通路增强胶质母细胞瘤的化疗敏感性并促进自噬
影响因子：
28.5
作者：
Li H;Chen L;Li JJ;Zhou Q;Huang A;Liu WW;Wang K;Gao L;Qi ST;Lu YT
通讯作者：
Lu YT
分子机制和血管生成的临床应用。
影响因子：
64.8
作者：
Carmeliet, Peter;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.