Hepatoma cell-secreted exosomal microRNA-103 increases vascular permeability and promotes metastasis by targeting junction proteins
Hepatoma cell-secreted exosomal microRNA-103 increases vascular permeability and promotes metastasis by targeting junction proteins
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肝癌细胞分泌的外泌体 microRNA-103 通过靶向连接蛋白增加血管通透性并促进转移
DOI：
10.1002/hep.29920
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发表时间：
2018-10-01
期刊：
影响因子：
13.5
通讯作者：
Zhuang, Shi-Mei
中科院分区：
文献类型：
--
作者：
Fang, Jian-Hong;Zhang, Zi-Jun;Zhuang, Shi-Mei
血管通透性增加促进转移。新出现的证据表明，分泌型微小RNA（miRNAs）可能介导癌细胞与基质细胞之间的相互作用。到目前为止，分泌型miRNAs是否以及如何影响血管通透性仍不清楚。基于深度测序和定量PCR，我们发现血清中较高水平的miR - 103与肝细胞癌（HCC）较高的转移潜能相关。体外内皮通透性和跨内皮侵袭实验表明，来自高表达miR - 103的肝癌细胞的条件培养基或外泌体增加了内皮单层的通透性，但如果通过沉默ALIX和HRS阻断肝癌细胞的外泌体分泌，或者如果拮抗肝癌细胞或内皮细胞内的miR - 103，这种作用就会减弱。最重要的是，用来自稳定表达miR - 103的肝癌细胞的外泌体预处理内皮单层促进了肿瘤细胞的跨内皮侵袭，并且通过抑制内皮细胞中的miR - 103消除了外泌体的这种作用。进一步的体内分析显示，与对照小鼠相比，接种稳定表达miR - 103的肝癌细胞的异种移植小鼠在肿瘤中表现出更高的血管通透性、更高水平的外泌体miR - 103以及血液循环中更多的肿瘤细胞，并且肝转移和肺转移的发生率增加。机制研究表明，肝癌细胞分泌的miR - 103可通过外泌体传递到内皮细胞，然后通过直接抑制血管内皮钙黏蛋白（VE - Cad）、p120 - 连环蛋白（p120）和紧密连接蛋白1的表达来削弱内皮连接的完整性。此外，miR - 103还可通过抑制肝癌细胞中p120的表达来促进肿瘤细胞迁移。结论：肝癌细胞分泌的外泌体miR - 103通过靶向多种内皮连接蛋白增加血管通透性并促进肿瘤转移，这突出表明分泌型miR - 103是肝细胞癌转移的潜在治疗靶点和预测标志物。（《肝脏病学》2018年）
Increased vascular permeability facilitates metastasis. Emerging evidence indicates that secreted microRNAs (miRNAs) may mediate the crosstalk between cancer and stromal cells. To date, whether and how secreted miRNAs affect vascular permeability remains unclear. Based on deep sequencing and quantitative PCR, we found that higher level of serum miR-103 was associated with higher metastasis potential of hepatocellular carcinoma (HCC). The in vitro endothelial permeability and transendothelial invasion assays revealed that the conditioned media or exosomes derived from high miR-103-expressing hepatoma cells increased the permeability of endothelial monolayers, but this effect was attenuated if exosome secretion of hepatoma cells was blocked by silencing ALIX and HRS or if miR-103 within hepatoma or endothelial cells was antagonized. Most importantly, pretreating endothelial monolayers with exosomes that were from stable miR-103-expressing hepatoma cells facilitated the transendothelial invasion of tumor cells, and this role of exosomes was abrogated by inhibiting miR-103 in endothelial cells. Further in vivo analyses disclosed that mice with xenografts of stable miR-103-expressing hepatoma cells exhibited higher vascular permeability in tumor, higher level of exosomal miR-103 and greater number of tumor cells in blood circulation, and increased rates of hepatic and pulmonary metastases, compared to control mice. Mechanism investigations revealed that hepatoma cell-secreted miR-103 could be delivered into endothelial cells via exosomes, and then attenuated the endothelial junction integrity by directly inhibiting the expression of VE-Cadherin (VE-Cad), p120-catenin (p120) and zonula occludens 1. Moreover, miR-103 could also promote tumor cell migration by repressing p120 expression in hepatoma cells. Conclusion: Hepatoma cell-secreted exosomal miR-103 increases vascular permeability and promotes tumor metastasis by targeting multiple endothelial junction proteins, which highlights secreted miR-103 as a potential therapeutic target and a predictive marker for HCC metastasis. (Hepatology 2018).