The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China.
School of Life and Science, Nanchang University, Nanchang, China.
J Cell Mol Med. 2020 Sep;24(18):10525-10541. doi: 10.1111/jcmm.15668. Epub 2020 Aug 14.
Hepatocellular carcinoma (HCC) is the third leading cause of the cancer-related death in the world. Human amniotic mesenchymal stem cells (hAMSCs) have been characterized with a pluripotency, low immunogenicity and no tumorigenicity. Especially, the immunosuppressive and anti-inflammatory effects of hAMSCs make them suitable for treating HCC. Here, we reported that hAMSCs administrated by intravenous injection significantly inhibited HCC through suppressing cell proliferation and inducing cell apoptosis in tumour-bearing mice with Hepg2 cells. Cell tracking experiments with GFP-labelled hAMSCs showed that the stem cells possessed the ability of migrating to the tumorigenic sites for suppressing tumour growth. Importantly, both hAMSCs and the conditional media (hAMSC-CM) have the similar antitumour effects in vitro, suggesting that hAMSCs-derived cytokines might be involved in their antitumour effects. Antibody array assay showed that hAMSCs highly expressed dickkopf-3 (DKK-3), dickkopf-1 (DKK-1) and insulin-like growth factor-binding protein 3 (IGFBP-3). Furthermore, the antitumour effects of hAMSCs were further confirmed by applications of the antibodies or the specific siRNAs of DKK-3, DKK-1 and IGFBP-3 in vitro. Mechanically, hAMSCs-derived DKK-3, DKK-1 and IGFBP-3 markedly inhibited cell proliferation and promoted apoptosis of Hepg2 cells through suppressing the Wnt/β-catenin signalling pathway and IGF-1R-mediated PI3K/AKT signalling pathway, respectively. Taken together, our study demonstrated that hAMSCs possess significant antitumour effects in vivo and in vitro and might provide a novel strategy for HCC treatment clinically.
肝细胞癌 (HCC) 是全球癌症相关死亡的第三大原因。人羊膜间充质干细胞 (hAMSCs) 具有多能性、低免疫原性和无致瘤性。特别是 hAMSCs 的免疫抑制和抗炎作用使其适合治疗 HCC。在这里，我们报道静脉注射 hAMSCs 通过抑制荷瘤小鼠 Hepg2 细胞中的细胞增殖和诱导细胞凋亡来显著抑制 HCC。用 GFP 标记的 hAMSCs 进行的细胞追踪实验表明，干细胞具有迁移到肿瘤部位抑制肿瘤生长的能力。重要的是，hAMSCs 和条件培养基 (hAMSC-CM) 在体外均具有相似的抗肿瘤作用，表明 hAMSCs 衍生的细胞因子可能参与其抗肿瘤作用。抗体阵列分析表明，hAMSCs 高度表达 Dickkopf-3 (DKK-3)、Dickkopf-1 (DKK-1) 和胰岛素样生长因子结合蛋白 3 (IGFBP-3)。此外，通过在体外应用 DKK-3、DKK-1 和 IGFBP-3 的抗体或特异性 siRNAs，进一步证实了 hAMSCs 的抗肿瘤作用。在机制上，hAMSCs 衍生的 DKK-3、DKK-1 和 IGFBP-3 通过抑制 Wnt/β-catenin 信号通路和 IGF-1R 介导的 PI3K/AKT 信号通路，显著抑制 Hepg2 细胞的增殖并促进其凋亡。综上所述，我们的研究表明 hAMSCs 在体内和体外均具有显著的抗肿瘤作用，可能为 HCC 的临床治疗提供新策略。
