EMT-cancer cells-derived exosomal miR-27b-3p promotes circulating tumour cells-mediated metastasis by modulating vascular permeability in colorectal cancer

Clin Transl Med. 2021 Dec;11(12):e595. doi: 10.1002/ctm2.595.

Abstract

Background: Metastasis is the main cause of death in colorectal cancer (CRC). Circulating tumour cells (CTCs) are regarded as the precursor cells of metastasis. The CTCs, which underwent epithelial-mesenchymal transition (EMT), are associated with metastasis and responsible for poor prognosis. EMT cancer cells modulate endothelial permeability in the invasive front and facilitate cancer cell intravasation, resulting in CTCs-mediated distant metastasis. Exosomes derived from cancer cells are key mediators of cancer-host intercommunication. However, the mechanism by which EMT-tumour cells-derived exosomes modulate vascular permeability and promote CTCs generation has remained unclear.

Methods: Exosomes isolation and purification were conducted by ultra-centrifugation. Exosomal miRNA was identified by sequencing followed by quantitative PCR. In vitro co-culture assay experiments were conducted to evaluate the effect of exosomal miR-27b-3p on the permeability of blood vessel endothelium. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP) and RNA immunoprecipitation (RIP) were performed to investigate the underlying mechanism by which miR-27b-3p is packaged into exosomes. A mouse model was established to determine the role of exosomal miR-27b-3p in blood vessel permeability modulation in vivo.

Results: We found that EMT-CRC cells attenuate the blood vessel barrier by transferring miR-27b-3p to human umbilical vein endothelial cells (HUVECs) in exosomes. Mechanically, miR-27b-3p atteuated the expression of vascular endothelial cadherin (VE-Cad) and p120 at the post-transcriptional level by binding to 3'-untranslated region of VE-Cad and p120 directly. The packaging of miR-27b-3p into exosomes was induced by heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), which activated by STAT3. Clinically, miR-27b-3p up-regulated in CRC tissues. Plasma exosomal miR-27b-3p was positively correlated with malignant progression and CTC count in CRC patients. Our study reveals a novel mechanism by which EMT-CRC cells promote metastasis, increasing blood vessel permeability and facilitating the generation of CTCs.

Conclusion: Exosomal miR-27b-3p secreted by EMT-CRC cells increases blood vessel permeability and facilitates the generation of CTCs. Exosomal miR-27b-3p may become a promising biomarker for CRC metastasis.

Keywords: CTCs; EMT; colorectal cancer; exosomes; metastasis; miR-27b-3p.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Capillary Permeability / physiology*
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Colorectal Neoplasms / complications
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / physiopathology*
  • Epithelial-Mesenchymal Transition / genetics*
  • Epithelial-Mesenchymal Transition / physiology
  • Female
  • Humans
  • Male
  • MicroRNAs / analysis
  • MicroRNAs / genetics
  • Middle Aged
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / physiopathology
  • Neoplastic Cells, Circulating

Substances

  • MIRN27b microRNA, human
  • MicroRNAs