Abstract
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.
Highlights
Cholangiocarcinoma (CCA) is a tumor originating in the epithelium of bile ducts and classified as intrahepatic, extrahepatic or perihilar according to different anatomical locations [1]
We investigated whether incubation with 10 ng/ml transforming growth factor-β (TGF-β) can induce Epithelial-mesenchymal transition (EMT) in CCA cells
We confirmed that the epithelial marker E-cadherin was decreased and that the EMTinducible transcription factor, Snail and mesenchymal markers, N-cadherin and Vimentin were increased after 10 ng/ml TGF-β treatment in CCA cells (Figure 1A)
Summary
Cholangiocarcinoma (CCA) is a tumor originating in the epithelium of bile ducts and classified as intrahepatic, extrahepatic or perihilar according to different anatomical locations [1]. Tumor cells, including CCA, with epithelial characteristics exhibit significantly enhanced invasion and migration abilities after EMT [4]. EMT is promoted by transcription factors such as Snail, Slug, Twist, ZEB1 and ZEB2 [5,6,7,8], and is characterized by a reduction of epithelial markers, including E-cadherin, and the induction of mesenchymal markers such as N-cadherin and Vimentin [9]. Transforming growth factor-β (TGF-β) is a strong EMT-inducer [9], and a recent study reported that human CCA cells undergo EMT via Snail activation by TGF-β [11]. EMT is an essential process for invasion and metastasis and inhibiting this pathway could improve the prognosis of CCA patients
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