Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran.
Int J Pharm. 2022 Nov 5;627:122214. doi: 10.1016/j.ijpharm.2022.122214. Epub 2022 Sep 21.
Exosomes derived from mesenchymal stem cells (MSCs) are mostly responsible for the therapeutic effects of MSCs. To show the therapeutic effects of the human bone marrow MSC-derived exosomes (MSC-Exos) on colorectal cancer (CRC) and explore the molecular cross-talks between them, CRC cells were treated with the MSC-Exos. We found that MSC-Exos were enriched with miR-100 and miR-143, which effectively downregulated mTOR, Cyclin D1, K-RAS, HK2 while upregulated p-27 expression. All these effects were reversed by concurrent treatment with MSC-Exos and antagomiR-100, confirming that they were caused by exosomal transfer of miR-100 into recipient CRC cells. Moreover, exosomal miR-100 promoted endogenous miR-143 expression. The flow cytometry, MTT and trypan blue assays revealed that MSC-Exos could efficiently suppress proliferation and induce apoptosis of the CRC cells. Furthermore, wound healing, transwell migration and invasion assays confirmed their inhibitory effects on the migration and invasiveness of SW480 cells. We further confirmed these effects by analyzing the expression levels of epithelial to mesenchymal transition (EMT) factors and metastasis-related genes. Results showed that MSC-Exos significantly suppressed the expression of MMP2 and MMP9 (metastasis-related genes), SNAIL and TWIST (EMT-inducing transcription factors), Vimentin and N-cadherin (mesenchymal cell markers), whereas E-cadherin (epithelial cell marker) was remarkably up-regulated. Collectively, our data indicated that MSC-Exos could suppress proliferation, migration, invasion and metastasis while inducing the apoptosis of the CRC cells via miR-100/mTOR/miR-143 axis. Our findings highlight that MSC-Exo treatment as well as miR-100 restoration might be considered as potential therapeutic strategies for CRC.
间充质干细胞（MSCs）衍生的外泌体主要负责 MSC 的治疗效果。为了展示人骨髓 MSC 衍生的外泌体（MSC-Exos）对结直肠癌（CRC）的治疗效果，并探讨它们之间的分子相互作用，用 MSC-Exos 处理 CRC 细胞。我们发现 MSC-Exos 富含 miR-100 和 miR-143，它们有效地下调了 mTOR、Cyclin D1、K-RAS、HK2，同时上调了 p-27 的表达。所有这些作用都被 MSC-Exos 和 antagomiR-100 的联合处理所逆转，证实它们是由外泌体将 miR-100 转移到受体 CRC 细胞中引起的。此外，外泌体 miR-100 促进了内源性 miR-143 的表达。流式细胞术、MTT 和台盼蓝检测表明，MSC-Exos 可有效抑制 CRC 细胞的增殖并诱导其凋亡。此外，划痕愈合、Transwell 迁移和侵袭实验证实了它们对 SW480 细胞迁移和侵袭的抑制作用。我们通过分析上皮间质转化（EMT）因子和转移相关基因的表达水平进一步证实了这些作用。结果表明，MSC-Exos 显著抑制了 MMP2 和 MMP9（转移相关基因）、SNAIL 和 TWIST（EMT 诱导转录因子）、Vimentin 和 N-cadherin（间充质细胞标志物）的表达，而 E-cadherin（上皮细胞标志物）则显著上调。总之，我们的数据表明，MSC-Exos 可通过 miR-100/mTOR/miR-143 轴抑制 CRC 细胞的增殖、迁移、侵袭和转移，同时诱导其凋亡。我们的研究结果表明，MSC-Exo 治疗以及 miR-100 的恢复可能被认为是 CRC 的潜在治疗策略。
