Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1

Nat Commun. 2016 Mar 29;7:11150. doi: 10.1038/ncomms11150.

Abstract

Advanced ovarian cancer usually spreads to the visceral adipose tissue of the omentum. However, the omental stromal cell-derived molecular determinants that modulate ovarian cancer growth have not been characterized. Here, using next-generation sequencing technology, we identify significantly higher levels of microRNA-21 (miR21) isomiRNAs in exosomes and tissue lysates isolated from cancer-associated adipocytes (CAAs) and fibroblasts (CAFs) than in those from ovarian cancer cells. Functional studies reveal that miR21 is transferred from CAAs or CAFs to the cancer cells, where it suppresses ovarian cancer apoptosis and confers chemoresistance by binding to its direct novel target, APAF1. These data suggest that the malignant phenotype of metastatic ovarian cancer cells can be altered by miR21 delivered by exosomes derived from neighbouring stromal cells in the omental tumour microenvironment, and that inhibiting the transfer of stromal-derived miR21 is an alternative modality in the treatment of metastatic and recurrent ovarian cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Adipocytes / pathology
  • Apoptosis / drug effects
  • Apoptotic Protease-Activating Factor 1 / metabolism*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Exosomes / drug effects
  • Exosomes / metabolism*
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • MicroRNAs / metabolism*
  • Neoplasm Invasiveness
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Paclitaxel / pharmacology*
  • Paclitaxel / therapeutic use
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism*

Substances

  • Apoptotic Protease-Activating Factor 1
  • MIRN21 microRNA, human
  • MicroRNAs
  • Paclitaxel