Exploring the potential of engineered exosomes as delivery systems for tumor-suppressor microRNA replacement therapy in ovarian cancer
Exploring the potential of engineered exosomes as delivery systems for tumor-suppressor microRNA replacement therapy in ovarian cancer
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DOI：
10.1016/j.bbrc.2020.04.076
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发表时间：
2020-06-18
影响因子：
3.1
通讯作者：
Kimura, Tadashi
中科院分区：
文献类型：
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作者：
Kobayashi, Masaki;Sawada, Kenjiro;Kimura, Tadashi
MicroRNA (miRNA) 在癌症生物学中发挥着关键作用。因此，肿瘤抑制（TS）miRNA 是癌症治疗的一个有吸引力的靶点。然而，由于 miRNA 递送的困难，临床试验失败了，需要开发一种新型药物递送系统 (DDS)。外泌体在循环中稳定并被癌细胞选择性摄取，表明它们可以作为 miRNA 载体。本研究的目的是探讨外泌体作为卵巢癌（OC）miRNA替代疗法载体的可能性。首先，从 OC 患者原代培养的网膜成纤维细胞中纯化外泌体。选择miR-199a-3p作为TS miRNA，通过电穿孔将合成的miR-199a-3p加载到外泌体中。用装载 miR199a-3p 的外泌体 (miR-199a-3p-Exo) 治疗可显着增加 OC 细胞系中 miR-199a-3p 的表达水平 (CaOV3; 8592-、SKOV3; 67188- 和 OVCAR3; 2280 倍)。 miR-199a-3p-Exo 抑制 c-Met 表达（miR-199a-3p 的直接靶标），从而抑制细胞增殖和侵袭。在一项异种移植研究中，miR-199a-3p-Exo 还显着抑制 OC 小鼠模型中的腹膜传播，并减少肿瘤中的 c-Met 表达、ERK 磷酸化和 MMP2 表达。这些结果表明，使用外泌体的 miRNA 替代疗法有望治疗 OC。鉴于大网膜成纤维细胞可以从大多数 OC 患者中获得，患者来源的外泌体可以用作未来分子靶向治疗的 DDS。 (c) 2020 Elsevier Inc. 保留所有权利。
MicroRNA (miRNA) plays a pivotal role in cancer biology. Therefore, tumor suppressor (TS) miRNAs are an attractive target for cancer therapy. However, clinical trials have failed due to the difficulties in miRNA delivery, warranting the development of a novel drug delivery system (DDS). Exosomes are stable in circulation and selectively picked up by cancer cells, indicating that they can serve as a miRNA carrier. The aim of this study was to explore the possibility of exosomes as a carrier for miRNA replacement therapy for ovarian cancer (OC). First, exosomes were purified from primary-cultured omental fibroblasts of OC patients. miR-199a-3p was selected as a TS miRNA, and the synthesized miR-199a-3p was loaded into exosomes by electroporation. Treatment with miR199a-3p-loaded-exosomes (miR-199a-3p-Exo) drastically increased miR-199a-3p expression level in OC cell lines (CaOV3; 8592-, SKOV3; 67188-, and OVCAR3; 2280-fold). miR-199a-3p-Exo suppressed c-Met expression, a direct target of miR-199a-3p, and thereby inhibited cell proliferation and invasion. In a xenograft study, miR-199a-3p-Exo also drastically inhibited peritoneal dissemination in OC mice model, and diminished c-Met expression, ERK phosphorylation, and MMP2 expression in tumors. These results suggest that miRNA replacement therapy using exosomes shows promise for treatment of OC. Given that omental fibroblasts can be obtained from most OC patients, patient-derived exosomes can be utilized as a DDS for future molecular-targeted therapies. (c) 2020 Elsevier Inc. All rights reserved.