Extracellular vesicles (EV) within the cellular secretome are emerging as modulators of pathological processes involved in tumor growth through their ability to transfer donor-derived RNA into recipient cells. While the effects of tumor and stromal cell EVs within the tumor microenvironment have been studied, less is known about the contributions of normal, nontransformed cells. We examined the impact of EVs within the cellular secretome from nonmalignant cells on transformed cell growth and behavior in cholangiocarcinoma cells. These effects were enhanced in the presence of the pro-fibrogenic mediator TGF-β. We identified miR-195 as a TGF-β responsive miRNA in normal cells that can be transferred via EV to tumor cells and regulate cell growth, invasion, and migration. The effects of miR-195 involve modulation of the epithelial–mesenchymal transition through direct effects on the transcription factor Snail. These studies provide in vitro and in vivo evidence for the impact of normal cellular secretome on transformed cell growth, show the importance of EV RNA transfer, and identify mechanisms of EV-mediated transfer of miRNA as a contributor to tumor development, which may provide new therapeutic opportunities for targeting human cholangiocarcinoma.

中文翻译：

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来自非恶性人胆管细胞的细胞外 RNA 转移可促进胆管癌的生长

细胞分泌组内的细胞外囊泡 (EV) 通过将供体来源的 RNA 转移到受体细胞中的能力，正在成为参与肿瘤生长的病理过程的调节剂。虽然已经研究了肿瘤和基质细胞 EV 在肿瘤微环境中的影响，但对正常的非转化细胞的贡献知之甚少。我们检查了来自非恶性细胞的细胞分泌组内的 EV 对胆管癌细胞中转化细胞生长和行为的影响。这些作用在促纤维化介质 TGF-β 存在下得到增强。我们将 miR-195 鉴定为正常细胞中的 TGF-β 响应 miRNA，可通过 EV 转移至肿瘤细胞并调节细胞生长、侵袭和迁移。miR-195 的作用涉及通过对转录因子 Snail 的直接作用来调节上皮-间质转化。这些研究提供体外和体内证据表明正常细胞分泌组对转化细胞生长的影响，显示了 EV RNA 转移的重要性，并确定了 EV 介导的 miRNA 转移作为肿瘤发展的贡献者的机制，这可能为肿瘤发展提供新的治疗机会靶向人类胆管癌。