BACKGROUND Mesenchymal stem cells (MSCs) are pluripotent mesenchymal cells present in various adult tissues. MSCs secrete exosomes as regulators of the tumor niche, with involvement in tumorigenesis and metastasis. The regulatory role of microRNAs (miRs or miRNAs) in MSCs via targeting cyclin E1 (CCNE1) or cyclin E2 (CCNE2) has been extensively reported. Since exosomes are considered as protective and enriched sources of shuttle miRNAs, we hypothesized that exosomal transfer of miR-144 from bone marrow-derived MSCs (BMMSCs) would affect the development of non-small cell lung cancer (NSCLC) cells by targeting CCNE1 and CCNE2. METHODS We first quantified the levels of miR-144, CCNE1, and CCNE2 in NSCLC tissues and cell lines and then undertook gain- and loss-of-function studies of miR-144, CCNE1, and CCNE2 to investigate their roles in the biological characteristics of NSCLC in vitro. NSCLC cells (A549) were exposed to exosomes derived from MSCs, and cell proliferation and colony formation rate were determined using in vitro assays. Finally, effects of BMMSC-derived exosomal miR-144 on tumor development were studied in vivo. RESULTS In NSCLC tissues and cell lines, miR-144 was expressed poorly and CCNE1 and CCNE2 were expressed highly. Artificially elevating miR-144 inhibited cell proliferation, colony formation, and the number of S phase-arrested cells in NSCLC by downregulating CCNE1 and CCNE2. Additionally, BMMSC-derived exosomal miR-144 led to restrained NSCLC cell proliferation and colony formation. These inhibitory effects of BMMSC-derived exosomes carrying miR-144 on NSCLC were confirmed by experiments in vivo. CONCLUSION Collectively, these findings revealed inhibitory effects of BMMSC-derived exosomal miR-144 on NSCLC progression, which were mediated by downregulation of CCNE1 and CCNE2.

中文翻译：

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来自骨髓间充质干细胞的外泌体 microRNA-144 通过靶向 CCNE1 和 CCNE2 抑制非小细胞肺癌的进展。

背景技术间充质干细胞(MSC)是存在于各种成人组织中的多能间充质细胞。间充质干细胞分泌外泌体作为肿瘤生态位的调节剂，参与肿瘤发生和转移。microRNAs（miRs或miRNAs）通过靶向细胞周期蛋白E1（CCNE1）或细胞周期蛋白E2（CCNE2）在MSCs中的调节作用已被广泛报道。由于外泌体被认为是穿梭 miRNA 的保护性和富集来源，我们假设 miR-144 从骨髓来源的 MSCs (BMMSCs) 的外泌体转移将通过靶向 CCNE1 和CCNE2。方法 我们首先量化了 NSCLC 组织和细胞系中 miR-144、CCNE1 和 CCNE2 的水平，然后对 miR-144、CCNE1、和 CCNE2 研究它们在体外 NSCLC 生物学特征中的作用。将 NSCLC 细胞 (A549) 暴露于源自 MSCs 的外泌体，并使用体外测定法测定细胞增殖和集落形成率。最后，在体内研究了 BMMSC 衍生的外泌体 miR-144 对肿瘤发展的影响。结果在NSCLC组织和细胞系中，miR-144低表达，CCNE1和CCNE2高表达。人为提高 miR-144 通过下调 CCNE1 和 CCNE2 来抑制 NSCLC 中的细胞增殖、集落形成和 S 期停滞细胞的数量。此外，BMMSC 衍生的外泌体 miR-144 导致 NSCLC 细胞增殖和集落形成受到抑制。携带 miR-144 的 BMMSC 衍生的外泌体对 NSCLC 的这些抑制作用已通过体内实验得到证实。