Jia Yuefeng, Ding Xuemei, Zhou Lihua, Zhang Li, Yang Xuecheng
Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, PR China.
Department of Surgery, The Affiliated Hospital of Qingdao University, Qingdao, 266003, PR China.
Oncogene. 2021 Jan;40(2):246-261. doi: 10.1038/s41388-020-01486-7. Epub 2020 Oct 29.
microRNAs (miRNAs) can be delivered to tumor cells where they exert their function via mesenchymal stem cells (MSCs)-derived exosomes. This study investigated exosomal transfer of miR-139-5p to bladder cancer cells and their role in the regulation of tumorigenesis. The dysregulation of polycomb repressor complex 1 (PRC1) in bladder cancer was characterized by RNA quantification, and its functional significance in bladder cancer cells was identified by loss-of-function experiments. We predicted the miR-139-5p that could play a role in regulating PRC1, which was further verified using dual-luciferase reporter gene assay. Next, we altered the expression of miR-139-5p and PRC1 in bladder cancer cells to identify their functions in cancer progression. Bladder cancer cells were co-cultured with exosomes isolated from human umbilical cord mesenchymal stem cells (hUCMSCs) over-expressing miR-139-5p. The intercellular transfer of miR-139-5p along with in vitro and in vivo functions was determined using gain- and loss-of-function approaches. Our results revealed that PRC1 levels were increased in bladder cancer tissues and cells, and silencing PRC1 appeared to impede the cell proliferation, migration, and invasion potentials. In addition, miR-139-5p was observed to be down-regulated in bladder cancer, which targeted PRC1 and reduced its expression, hereby resulting in ameliorated tumorigenic characteristics of bladder cancer cells in vitro. Furthermore, we noted that miR-139-5p from hUCMSCs-derived exosomes could be transferred into bladder cancer cells to down-regulate the PRC1 expression. Moreover, hUCMSCs-derived exosomal miR-139-5p conferred a suppressive role on bladder cancer development in vitro and in vivo. These data together supported the tumor-inhibiting role of MSCs-derived exosomal miR-139-5p in bladder cancer, highlighting a promising therapeutic strategy.
微小RNA（miRNA）可通过间充质干细胞（MSC）衍生的外泌体传递至肿瘤细胞并发挥其功能。本研究调查了miR-139-5p向外泌体的转移及其在膀胱癌细胞中的作用，以及它们在肿瘤发生调控中的作用。通过RNA定量分析了膀胱癌中多梳抑制复合物1（PRC1）的失调情况，并通过功能缺失实验确定了其在膀胱癌细胞中的功能意义。我们预测miR-139-5p可能在调节PRC1中发挥作用，并使用双荧光素酶报告基因检测进一步验证。接下来，我们改变了膀胱癌细胞中miR-139-5p和PRC1的表达，以确定它们在癌症进展中的功能。将膀胱癌细胞与从过表达miR-139-5p的人脐带间充质干细胞（hUCMSC）中分离的外泌体共培养。使用功能获得和功能缺失方法确定了miR-139-5p的细胞间转移及其体外和体内功能。我们的结果显示，PRC1水平在膀胱癌组织和细胞中升高，沉默PRC1似乎会阻碍细胞增殖、迁移和侵袭潜力。此外，观察到miR-139-5p在膀胱癌中下调，其靶向PRC1并降低其表达，从而导致膀胱癌细胞在体外的致瘤特性得到改善。此外，我们注意到来自hUCMSC衍生外泌体的miR-139-5p可以转移到膀胱癌细胞中以下调PRC1表达。此外，hUCMSC衍生的外泌体miR-139-5p在体外和体内对膀胱癌的发展具有抑制作用。这些数据共同支持了MSC衍生的外泌体miR-139-5p在膀胱癌中的肿瘤抑制作用，突出了一种有前景的治疗策略。
