Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma.
Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma.
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源自 miR-122 修饰的脂肪组织来源的 MSC 的外泌体可增加肝细胞癌的化疗敏感性
DOI：
10.1186/s13045-015-0220-7
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发表时间：
2015-10-29
影响因子：
28.5
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Lou G;Song X;Yang F;Wu S;Wang J;Chen Z;Liu Y
背景肝细胞癌（Hepatocellular carcinoma，HCC）对常规化疗具有较高的耐药性.考虑到microRNA-122（miR-122）在促进HCC细胞的化疗敏感性方面发挥重要作用，有效的载体介导的miR-122递送可能代表HCC化疗的有希望的策略。越来越多的兴趣集中在使用外来体作为微RNA（miRNA）转移的生物载体。间充质干细胞（MSC）以其产生大量外泌体的能力而闻名。本研究旨在确定脂肪组织来源的MSC（AMSC）外泌体是否可用于miR-122 delivery. MethodsAMSC用miR-122表达质粒转染。在转染后48小时，收获AMSC衍生的外泌体（122-Exo）并添加到受体HCC细胞中。通过实时PCR定量AMSC、外来体和HCC细胞中miR-122的表达水平。分别通过实时定量PCR和Western blot定量受体HCC细胞中miR-122靶基因的mRNA和蛋白水平。采用MTT法和流式细胞仪检测122-Exo对肝癌细胞活力、凋亡和细胞周期的影响。结果miR-122转染的AMSC能有效地将miR-122包装到分泌的exosomes中，从而介导AMSC和HCC细胞之间的miR-122通讯，从而通过改变HCC细胞中miR-122靶基因的表达使癌细胞对化疗药物敏感。此外，肿瘤内注射122-Exo显着增加索拉非尼对HCC的抗肿瘤疗效invivo.ConclusionsThe研究结果表明，出口的miR-122通过AMSC exosomes代表了一种新的策略，以提高肝癌化疗敏感性。
BackgroundHepatocellular carcinoma (HCC) displays high resistance to conventional chemotherapy. Considering that microRNA-122 (miR-122) performs an essential function to promote chemosensitivity of HCC cells, an effective vehicle-mediated miR-122 delivery may represent a promising strategy for HCC chemotherapy. An increasing interest is focused on the use of exosomes as biological vehicles for microRNAs (miRNA) transfer. Mesenchymal stem cells (MSCs) are known for their capacity to produce large amounts of exosomes. This study aimed to determine whether adipose tissue-derived MSC (AMSC) exosomes can be used for miR-122 delivery.MethodsAMSCs were transfected with a miR-122 expression plasmid. At 48 h after transfection, AMSC-derived exosomes (122-Exo) were harvested and added to recipient HCC cells. Expression levels of miR-122 in AMSCs, exosomes, and HCC cells were quantified by real-time PCR. The mRNA and protein levels of miR-122-target genes in recipient HCC cells were quantified by real-time PCR and Western blot, respectively. The effects of 122-Exo on cell viability, apoptosis, and cell cycle of HCC cells were evaluated by MTT and flow cytometry analysis. Xenograft models were used to determine whether 122-Exo can sensitize HCC cells to sorafenib in vivo.ResultsData showed that miR-122-transfected AMSC can effectively package miR-122 into secreted exosomes, which can mediate miR-122 communication between AMSCs and HCC cells, thereby rendering cancer cells sensitive to chemotherapeutic agents through alteration of miR-122-target gene expression in HCC cells. Moreover, intra-tumor injection of 122-Exo significantly increased the antitumor efficacy of sorafenib on HCC in vivo.ConclusionsThe findings suggest that the export of miR-122 via AMSC exosomes represents a novel strategy to enhance HCC chemosensitivity.