Extracellular Vesicles-Encapsulated MicroRNA-125b Produced in Genetically Modified Mesenchymal Stromal Cells Inhibits Hepatocellular Carcinoma Cell Proliferation
Extracellular Vesicles-Encapsulated MicroRNA-125b Produced in Genetically Modified Mesenchymal Stromal Cells Inhibits Hepatocellular Carcinoma Cell Proliferation
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基因改造的间充质基质细胞产生的细胞外囊泡包裹的微小核糖核酸-125b抑制肝癌细胞增殖
DOI：
10.3390/cells8121560
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发表时间：
2019-12-01
期刊：
影响因子：
6
通讯作者：
Toietta, Gabriele
中科院分区：
文献类型：
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作者：
Baldari, Silvia;Di Rocco, Giuliana;Toietta, Gabriele
肝细胞癌（HCC）是最常见的原发性肝癌类型，也是癌症死亡的主要原因之一，全球每年约有780，000人死亡。microRNA-125 b（miR-125 b）的下调是HCC患者的预后指标。相反，miR-125 b在HCC细胞中的过表达诱导细胞周期停滞，抑制增殖、迁移和侵袭。细胞外囊泡（EV）作为细胞间信使起作用，传递蛋白质、RNA、DNA、碳水化合物和脂质。由于EV保护其货物免于降解，因此通过EV递送治疗性生物活性分子，特别是miRNA，代表了癌症治疗的创新途径。在这项研究中，我们评估了一种治疗HCC的替代策略，通过递送从人脂肪组织来源的间充质基质/药物信号传导细胞（ASC）分泌的EV，该细胞用表达miR-125 b的慢病毒载体进行遗传修饰，该慢病毒载体具有特异性ExoMotif序列标签以增强细胞外囊泡的装载。特别地，我们确定了在工程化ASC中产生的miR-125 b负载的EV的递送特异性地降低了HCC细胞体外增殖，调节了一系列属于p53信号传导途径的miR-125 b靶标。这项概念验证研究支持通过EV介导的miRNA递送开发HCC的创新治疗策略。
Hepatocellular carcinoma (HCC) is the most frequent type of primary liver cancer and one of the prominent causes of cancer mortality, leading to approximately 780,000 deaths per year worldwide. Down-regulation of microRNA-125b (miR-125b) is a prognostic indicator in HCC patients. Conversely, over-expression of miR-125b in HCC cells induces cell cycle arrest, inhibits proliferation, migration and invasion. Extracellular vesicles (EVs) function as intercellular messengers transferring proteins, RNAs, DNAs, carbohydrates, and lipids. Since EVs protect their cargo from degradation, delivery of therapeutic bioactive molecules, in particular miRNAs, through EVs represents an innovative avenue for cancer therapy. In this study, we evaluated a replacement strategy for the treatment of HCC via delivery of EVs secreted from human adipose tissue-derived mesenchymal stromal/medicinal signaling cells (ASCs) genetically modified with a lentiviral vector expressing miR-125b with a specific ExoMotif sequence tag to enhance the loading into extracellular vesicles. In particular, we determined that the delivery of miR-125b-loaded EVs produced in engineered ASCs specifically reduces HCC cell proliferation in vitro modulating a series of miR-125b targets, which belong to the p53 signaling pathway. This proof-of-concept study supports the development of innovative therapeutic strategies for HCC via EV-mediated miRNA delivery.