Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia and remains incurable. Mesenchymal stem cells (MSCs) can promote tumor progression by differentiating into cancer-associated fibroblasts (CAFs). However, the mechanisms by which tumor cells induce the transition of MSCs to CAFs are still largely undefined. Exosomes can regulate recipient cellular function by mediating intracellular communication. This study aimed to investigate whether CLL cells regulates the transition of bone marrow-derived MSCs (BM-MSCs) to CAFs via exosomal miR-146a delivery. The exosomes were isolated from CLL cell line MEC-1 (CLL-Exo) and then co-cultured with BM-MSCs. The expression of α-smooth muscle actin (α-SMA) and fibroblast activated protein (FAP) were determined by immunofluorescence, qRT-PCR and western blot. A luciferase reporter assay was performed to verify whether ubiquitin specific peptidase 16 (USP16) was a target of miR-146a. CLL-Exo treatment upregulated miR-146a and downregulated expression of CAF markers (α-SMA, FAP) and USP16. The inducing effect of CLL-Exo on CAF marker expression was compromised when miR-146a expression was inhibited in CLL-Exo. USP16 was confirmed as a direct target of miR-146a and USP16 overexpression in BM-MSCs abrogated the CLL-Exo-mediated upregulation of CAF markers. Collectively, CLL-Exo delivered miR-146a into BM-MSCs where miR-146a mediated transition of BM-MSCs into CAFs by targeting USP16.

中文翻译：

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源自慢性淋巴细胞性白血病细胞的外泌体转移miR-146a，诱导间充质基质细胞向癌症相关的成纤维细胞过渡。

慢性淋巴细胞性白血病（CLL）是最普遍的白血病，仍然无法治愈。间充质干细胞（MSC）可以分化为癌症相关的成纤维细胞（CAF），从而促进肿瘤的进展。但是，肿瘤细胞诱导MSC转变为CAF的机制仍很不确定。外来体可以通过介导细胞内通讯来调节受体的细胞功能。这项研究旨在研究CLL细胞是否通过外泌体miR-146a传递来调节骨髓来源的MSC（BM-MSC）向CAF的过渡。从CLL细胞系MEC-1（CLL-Exo）中分离外泌体，然后与BM-MSC共培养。通过免疫荧光，qRT-PCR和western blot检测α-平滑肌肌动蛋白（α-SMA）和成纤维细胞活化蛋白（FAP）的表达。进行荧光素酶报告基因分析以验证泛素特异性肽酶16（USP16）是否是miR-146a的靶标。CLL-Exo治疗上调了miR-146a，下调了CAF标记（α-SMA，FAP）和USP16的表达。当在CLL-Exo中抑制miR-146a表达时，CLL-Exo对CAF标志物表达的诱导作用受到损害。USP16被证实是miR-146a的直接靶标，而USP16在BM-MSC中的过表达消除了CLL-Exo介导的CAF标记的上调。总的来说，CLL-Exo将miR-146a传递到BM-MSC，其中miR-146a通过靶向USP16介导BM-MSC到CAF的过渡。当在CLL-Exo中抑制miR-146a表达时，CLL-Exo对CAF标志物表达的诱导作用受到损害。USP16被证实是miR-146a的直接靶标，而USP16在BM-MSC中的过表达消除了CLL-Exo介导的CAF标记的上调。总的来说，CLL-Exo将miR-146a传递到BM-MSC，其中miR-146a通过靶向USP16介导BM-MSC到CAF的过渡。当在CLL-Exo中抑制miR-146a表达时，CLL-Exo对CAF标志物表达的诱导作用受到损害。USP16被证实是miR-146a的直接靶标，而BM-MSC中USP16的过表达消除了CLL-Exo介导的CAF标记的上调。总的来说，CLL-Exo将miR-146a传递到BM-MSC，其中miR-146a通过靶向USP16介导BM-MSC到CAF的过渡。