ABSTRACT

Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) expressing microRNAs (miRNAs) have been highlighted in human cancers. However, the detailed molecular mechanism of hucMSCs-derived exosomal miR-451a on hepatocellular carcinoma (HCC) remains further investigation. Our study aims to explore the impact of exosomal miR-451a on the progression of HCC. Expression of miR-451a and a disintegrin and metalloprotease 10 (ADAM10) in HCC tissues and adjacent normal tissues were determined. The exosomes were extracted from hucMSCs and co-cultured with Hep3B and SMMC-7721 cell lines. After the treatment of relative exosomes or exosome inhibitor GW4869 in Hep3B and SMMC-7721 cells, the paclitaxel resistance and malignant phenotypes of HCC cells were measured. Moreover, the effect of hucMSCs-derived exosomes on the expression of miR-451a and ADAM10 in HCC cells was assessed. The targeting relationship between miR-451a and ADAM10 was verified to detect the impact of ADAM10-wild type and ADAM10-mutant type (MUT) on HCC cell processes. Low expression of miR-451a and high expression of ADAM10 indicated a poor prognosis of HCC patients. MiR-451a was up-regulated while ADAM10 was down-regulated in HCC cells after co-culture with HucMSC-derived exosomes. The exosomes elevated miR-451a and inhibited ADAM10 to suppress the paclitaxel resistance, cell cycle transition, proliferation, migration and invasion, and promote apoptosis of HCC cells. ADAM10 was verified to be a target gene of miR-451a. ADAM10-MUT promoted HCC process independent of miR-451a mimic. HucMSC-derived exosomal miR-451a could restrict the epithelial–mesenchymal transition of HCC cells by targeting ADAM10, which might provide new targets for HCC treatment.

摘要

来自人类脐带间充质干细胞 (hucMSCs) 的外泌体表达 microRNAs (miRNAs) 已在人类癌症中突出显示。然而，hucMSCs衍生的外泌体miR-451a对肝细胞癌（HCC）的详细分子机制仍有待进一步研究。我们的研究旨在探索外泌体 miR-451a 对 HCC 进展的影响。测定了 HCC 组织和邻近正常组织中 miR-451a 和去整合素和金属蛋白酶 10 (ADAM10) 的表达。从 hucMSCs 中提取外泌体并与 Hep3B 和 SMMC-7721 细胞系共培养。在Hep3B和SMMC-7721细胞中处理相关外泌体或外泌体抑制剂GW4869后，测量HCC细胞的紫杉醇耐药性和恶性表型。而且，评估了hucMSCs衍生的外泌体对HCC细胞中miR-451a和ADAM10表达的影响。验证了 miR-451a 和 ADAM10 之间的靶向关系，以检测 ADAM10 野生型和 ADAM10 突变型 (MUT) 对 HCC 细胞过程的影响。miR-451a的低表达和ADAM10的高表达表明HCC患者预后不良。在与 HucMSC 衍生的外泌体共培养后，miR-451a 上调，而 ADAM10 在 HCC 细胞中下调。外泌体通过升高miR-451a和抑制ADAM10来抑制紫杉醇耐药、细胞周期转换、增殖、迁移和侵袭，促进HCC细胞凋亡。ADAM10 被证实是 miR-451a 的靶基因。ADAM10-MUT 促进了独立于 miR-451a 模拟物的 HCC 过程。