MSC-Derived exosomes suppress colorectal cancer cell proliferation and metastasis via miR-100/mTOR/miR-143 pathway

Int J Pharm. 2022 Nov 5;627:122214. doi: 10.1016/j.ijpharm.2022.122214. Epub 2022 Sep 21.

Abstract

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.

Keywords: Colorectal cancer; Exosomes; Mesenchymal stem cells; mTOR; miR-100; microRNAs.

MeSH terms

  • Antagomirs / metabolism
  • Cadherins / metabolism
  • Cell Movement
  • Cell Proliferation
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / metabolism
  • Colorectal Neoplasms* / therapy
  • Cyclin D1 / metabolism
  • Cyclin D1 / pharmacology
  • Epithelial-Mesenchymal Transition
  • Exosomes* / metabolism
  • Humans
  • Matrix Metalloproteinase 2 / metabolism
  • Matrix Metalloproteinase 2 / pharmacology
  • Matrix Metalloproteinase 9 / metabolism
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / metabolism
  • Trypan Blue / metabolism
  • Trypan Blue / pharmacology
  • Vimentin / metabolism
  • Vimentin / pharmacology

Substances

  • Matrix Metalloproteinase 9
  • Cyclin D1
  • Matrix Metalloproteinase 2
  • Vimentin
  • Antagomirs
  • Trypan Blue
  • MicroRNAs
  • TOR Serine-Threonine Kinases
  • Cadherins
  • Transcription Factors
  • MTOR protein, human
  • MIRN100 microRNA, human
  • MIRN143 microRNA, human