Ovarian cancer cell-secreted exosomal miR-205 promotes metastasis by inducing angiogenesis
Ovarian cancer cell-secreted exosomal miR-205 promotes metastasis by inducing angiogenesis
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DOI：
10.7150/thno.37455
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Wu, Xiaoying
中科院分区：
文献类型：
--
作者：
He, Liuqing;Zhu, Wei;Wu, Xiaoying
背景：肿瘤血管生成通过提供氧气、营养物质和转移通道，对肿瘤转移至关重要。癌细胞分泌的microRNA可以包装到外泌体中，并涉及肿瘤血管生成的不同方面。方法：应用GEPIA数据库和原位杂交技术分析卵巢组织中miR-205的表达情况。采用免疫组织化学方法检测miR-205与微血管密度的关系。通过RT-PCR和GEO数据库分析评估循环miR-205的表达。进行共培养和外泌体标记实验以评估外泌体miR-205从卵巢癌（OC）细胞转移至内皮细胞EC。采用外泌体摄取测定来定义与外泌体miR-205的内吞摄取相关的细胞途径。在体内和体外进一步研究了外泌体miR-205在血管生成中的作用。结果：miR-205在OC组织中表达上调，且miR-205高表达与OC的转移进展相关。此外，miR-205在癌旁EC中高度富集，并且miR-205的上调与OC患者的高微血管密度呈正相关。重要的是，miR-205在OC患者的血清中显著富集，并且循环外泌体中高水平的miR-205与OC转移相关。此外，OC衍生的miR-205分泌到细胞外空间，并以外泌体依赖性方式有效转移到相邻EC，并且脂筏相关途径在调节外泌体miR-205的摄取中起重要作用。来自OC细胞的外泌体miR-205显著促进体外血管生成并加速小鼠模型中的血管生成和肿瘤生长。结论：来源于癌细胞的外泌体miR-205通过PTEN-AKT通路调控肿瘤血管生成，提示外泌体miR-205可能是OC的潜在治疗靶点。
Background: By providing oxygen, nutrients and metastatic conduits, tumour angiogenesis is essential for cancer metastasis. Cancer cell-secreted microRNAs can be packaged into exosomes and are implicated in different aspects of tumour angiogenesis. However, the underlying mechanisms are incompletely understood.Methods: The GEPIA database and in situ hybridization assay were used to analyse expression of miR-205 in ovarian tissues. Immunohistochemistry was performed to examine the relationship between miR-205 and microvessel density. Expression of circulating miR-205 was evaluated by RT-PCR and GEO database analysis. Co-culture and exosome labelling experiments were performed to assess exosomal miR-205 transfer from ovarian cancer (OC) cells to endothelial cells ECs. Exosome uptake assays were employed to define the cellular pathways associated with the endocytic uptake of exosomal miR-205. The role of exosomal miR-205 in angiogenesis was further investigated in vivo and in vitro. Western blotting and rescue experiments were applied to detect regulation of the PTEN-AKT pathway by exosomal miR-205 in ECs.Results: miR-205 was up-regulated in OC tissues, and high expression of miR-205 was associated with metastatic progression in OC patients. Moreover, miR-205 was highly enriched in cancer-adjacent ECs, and up-regulation of miR-205 correlated positively with high microvessel density in OC patients. Importantly, miR-205 was markedly enriched in the serum of OC patients, and a high level of miR-205 in circulating exosomes was associated with OC metastasis. In addition, OC-derived miR-205 was secreted into the extracellular space and efficiently transferred to adjacent ECs in an exosome-dependent manner, and the lipid raft-associated pathway plays an important role in regulating uptake of exosomal miR-205. Exosomal miR-205 from OC cells significantly promoted in vitro angiogenesis and accelerated angiogenesis and tumour growth in a mouse model. Furthermore, we found that exosomal miR-205 induces angiogenesis via the PTEN-AKT pathway.Conclusion: These findings demonstrate an exosome-dependent mechanism by which miR-205 derived from cancer cells regulates tumour angiogenesis and implicate exosomal miR-205 as a potential therapeutic target for OC.