Extracellular vesicle-encapsulated miR-30e suppresses cholangiocarcinoma cell invasion and migration via inhibiting epithelial-mesenchymal transition.
Extracellular vesicle-encapsulated miR-30e suppresses cholangiocarcinoma cell invasion and migration via inhibiting epithelial-mesenchymal transition.
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DOI：
10.18632/oncotarget.24711
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发表时间：
2018-03-27
期刊：
影响因子：
--
通讯作者：
Haneda M
中科院分区：
文献类型：
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作者：
Ota Y;Takahashi K;Otake S;Tamaki Y;Okada M;Aso K;Makino Y;Fujii S;Ota T;Haneda M
早期胆管癌（CCA）由于其高侵袭和转移潜力而难以诊断。上皮-间质转化（EMT）是由转化生长因子-β（TGF-β）诱导的，在包括CCA在内的几种癌症中，这一过程被认为对侵袭和转移很重要。尽管microRNA（miRNAs）参与了多种恶性肿瘤的发病机制，但其在CCA中的作用尚不清楚。据报道，一些miRNA被包含在细胞外囊泡（EV）中，并从其供体细胞转移到其他细胞，调节受体细胞的行为。在这项研究中，包含EV的miRNA在人类CCA的EMT过程中的参与和功能作用被确定。表达谱分析鉴定了CCA细胞中TGF-β减少的miRNA子集。其中，miR-30 e被TGF-β高度下调，并预测靶向Snail，Snail是一种EMT诱导型转录因子。miR-30 e过表达通过抑制EMT抑制细胞侵袭和迁移，而miR-30 e抑制则促进EMT、细胞侵袭和迁移。此外，miR-30 e过表达后，miR-30 e在源自CCA细胞的EV中富集，并且miR-30 e通过EV的细胞间转移抑制受体CCA细胞中的EMT、细胞侵袭和迁移。总之，我们的研究结果表明，EV介导的miR-30 e转移可以通过直接靶向Snail抑制EMT，从而抑制CCA细胞的侵袭和迁移。这些发现为研究人类CCA中肿瘤侵袭和转移的调控机制提供了一些新的见解。
Early-staged cholangiocarcinoma (CCA) is difficult to diagnose due to its high potential for invasion and metastasis. Epithelial-mesenchymal transition (EMT) is induced by transforming growth factor-β (TGF-β) in a process thought to be important for invasion and metastasis in several cancers, including CCA. Although microRNAs (miRNAs) have been implicated in the pathogenesis of several malignancies, their roles to CCA are not clearly understood. Some miRNAs were reported to be included in extracellular vesicles (EVs) and transferred from their donor cells to other cells, modulating recipient cell behaviors. In this study, the involvement and functional roles of EV-contained miRNAs during EMT in human CCA were determined. Expression profiling identified a subset of miRNAs that were reduced by TGF-β in CCA cells. Among these, miR-30e was highly downregulated by TGF-β and predicted to target Snail, which is an EMT-inducible transcription factor. MiR-30e overexpression suppressed cell invasion and migration via inhibiting EMT, whereas miR-30e inhibition promoted EMT, cell invasion and migration. Moreover, miR-30e was enriched in EVs derived from CCA cells after miR-30e overexpression, and miR-30e intercellular transfer through EVs suppressed EMT, cell invasion and migration in recipient CCA cells. Together, our results suggest that EV-mediated miR-30e transfer could inhibit EMT via directly targeting Snail, which subsequently suppresses CCA cell invasion and migration. These findings provide several new insights into regulatory mechanisms of tumor invasion and metastasis in human CCA.