miRNA-1246 in extracellular vesicles secreted from metastatic tumor induces drug resistance in tumor endothelial cells

Sci Rep. 2021 Jul 5;11(1):13502. doi: 10.1038/s41598-021-92879-5.


Tumor endothelial cells (TECs) reportedly exhibit altered phenotypes. We have demonstrated that TECs acquire drug resistance with the upregulation of P-glycoprotein (P-gp, ABCB1), contrary to traditional assumptions. Furthermore, P-gp expression was higher in TECs of highly metastatic tumors than in those of low metastatic tumors. However, the detailed mechanism of differential P-gp expression in TECs remains unclear. miRNA was identified in highly metastatic tumor extracellular vesicles (EVs) and the roles of miRNA in endothelial cell resistance were analyzed in vitro and in vivo. In the present study, we found that treatment of highly metastatic tumor-conditioned medium induced resistance to 5-fluorouracil (5-FU) with interleukin-6 (IL-6) upregulation in endothelial cells (ECs). Among the soluble factors secreted from highly metastatic tumors, we focused on EVs and determined that miR-1246 was contained at a higher level in highly metastatic tumor EVs than in low metastatic tumor EVs. Furthermore, miR-1246 was transported via the EVs into ECs and induced IL-6 expression. Upregulated IL-6 induced resistance to 5-FU with STAT3 and Akt activation in ECs in an autocrine manner. These results suggested that highly metastatic tumors induce drug resistance in ECs by transporting miR-1246 through EVs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Case-Control Studies
  • Cell Line
  • Drug Resistance, Neoplasm*
  • Endothelial Cells / metabolism
  • Extracellular Vesicles / metabolism*
  • Female
  • Interleukin-6 / metabolism
  • Melanoma / metabolism*
  • Mice, Nude
  • MicroRNAs / physiology*
  • Neoplasm Metastasis*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptors, Androgen / metabolism
  • STAT3 Transcription Factor / metabolism


  • IL6 protein, human
  • Interleukin-6
  • MIRN1246 microRNA, human
  • MicroRNAs
  • Receptors, Androgen
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Proto-Oncogene Proteins c-akt