靶向间质干细胞外泌体治疗微小 RNA-let-7c 递送来治疗去势抵抗性前列腺癌。
Targeting Castration-Resistant Prostate Cancer Using Mesenchymal Stem Cell Exosomes for Therapeutic MicroRNA-let-7c Delivery.
机构信息
International Ph.D. Program for Translational Science, College of Medical Science and Technology, Taipei Medical University, 110 Taipei, Taiwan.
Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, 110 Taipei, Taiwan.
出版信息
Front Biosci (Landmark Ed). 2022 Sep 6;27(9):256. doi: 10.31083/j.fbl2709256.
BACKGROUND
Castration-resistant prostate cancer (PCa; CRPC) has a poor response to androgen deprivation therapy and is considered an incurable disease. MicroRNA (miR)-lethal 7c (let-7c) was implied to be a tumor suppressor in PCa, and treatment with exogenous let-7c targets both cancer cells and their associated mesenchymal stem cells (MSCs) to prevent CRPC progression and metastasis. Exosomes are nanometer-sized membrane-bound vesicles which have an absolute predominance in biocompatibility for drug delivery and gene therapy by mediating cell-to-cell communication. By utilizing the intrinsic tumor-targeting property of MSCs, this study aimed to investigate the feasibility of MSC-derived exosomes as an exogenous miR delivery system to target CRPC, using miR let-7c as an example.
METHODS
Bioinformatics analysis was performed to observe miR-let-7c expression in clinical samples by utilizing the GEO database. MSC-derived exosomes were collected from a human bone marrow-derived MSC cell line after cell transfection with either a pre-miR negative control or pre-miR-let-7c, and further characterized through nanoparticle tracking analysis and Western blotting. miR-let-7c expression was determined using RT-qPCR, and the phenotypic effects of both naked and MSC-exosome-encapsulated let-7c on CRPC cells (PC3 and CWR22Rv1) were determined by WST-1 cell proliferation assay and wound healing migration assay.
RESULTS
miR-let-7c was downregulated in metastatic PCa and high grade group patients. miR-let-7c expression was confirmed to be downregulated in PCa cell lines, with massively decreased in most metastatic CRPC-like cells. Exogenous miR-let-7c can be successfully packaged into MSC exosomes. Treatment with either naked or MSC-exosome-encapsulated miR-let-7c resulted in significant reductions in cell proliferation and migration in CRPC-like PC3 and CWR22Rv1 cells.
CONCLUSIONS
MSC-derived exosomes could serve as a therapeutic let-7c delivery system to target CRPC.
背景
去势抵抗性前列腺癌（CRPC）对雄激素剥夺治疗反应不佳，被认为是一种无法治愈的疾病。microRNA（miR）-致死 7c（let-7c）被暗示为前列腺癌的肿瘤抑制因子，外源性 let-7c 靶向癌细胞及其相关的间充质干细胞（MSCs），以防止 CRPC 进展和转移。外泌体是纳米级的膜结合囊泡，通过介导细胞间通讯，在药物输送和基因治疗方面具有绝对的生物相容性优势。本研究利用 MSCs 的内在肿瘤靶向特性，旨在探讨 MSC 衍生的外泌体作为外源性 miR 递药系统靶向 CRPC 的可行性，以 let-7c 为例。
方法
通过利用 GEO 数据库进行生物信息学分析，观察临床样本中 miR-let-7c 的表达。在转染了 pre-miR 阴性对照或 pre-miR-let-7c 的人骨髓源性 MSC 细胞系中收集 MSC 衍生的外泌体，并通过纳米颗粒跟踪分析和 Western blot 进一步进行表征。通过 RT-qPCR 确定 miR-let-7c 的表达，通过 WST-1 细胞增殖测定和划痕愈合迁移测定确定裸 miR-let-7c 和 MSC 外泌体包裹的 let-7c 对 CRPC 细胞（PC3 和 CWR22Rv1）的表型效应。
结果
miR-let-7c 在转移性前列腺癌和高分级组患者中下调。miR-let-7c 的表达在前列腺癌细胞系中被证实下调，在大多数转移性 CRPC 样细胞中明显减少。外源性 miR-let-7c 可成功包装到 MSC 外泌体中。裸 miR-let-7c 和 MSC 外泌体包裹的 miR-let-7c 处理均可显著降低 CRPC 样 PC3 和 CWR22Rv1 细胞的增殖和迁移。
结论
MSC 衍生的外泌体可以作为一种治疗性 let-7c 递药系统，靶向 CRPC。
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