Cell-based therapy using miR-302-367 expressing cells represses glioblastoma growth

Cell Death Dis. 2017 Mar 30;8(3):e2713. doi: 10.1038/cddis.2017.117.

Abstract

Glioblastomas are incurable primary brain tumors that affect patients of all ages. The aggressiveness of this cancer has been attributed in part to the persistence of treatment-resistant glioblastoma stem-like cells. We have previously discovered the tumor-suppressor properties of the microRNA cluster miR-302-367, representing a potential treatment for glioblastoma. Here, we attempted to develop a cell-based therapy by taking advantage of the capability of glioma cells to secrete exosomes that enclose small RNA molecules. We engineered primary glioma cells to stably express the miR-302-367. Remarkably, these cells altered, in a paracrine-dependent manner, the expression of stemness markers, the proliferation and the tumorigenicity of neighboring glioblastoma cells. Further characterization of the secretome derived from miR-302-367 expressing cells showed that a large amount of miR-302-367 was enclosed in exosomes, which were internalized by the neighboring glioblastoma cells. This miR-302-367 cell-to-cell transfer resulted in the inhibition of its targets such as CXCR4/SDF1, SHH, cyclin D, cyclin A and E2F1. Orthotopic xenograft of miR-302-367-expressing cells together with glioblastoma stem-like cells efficiently altered the tumor development in mice brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell- and Tissue-Based Therapy
  • Gene Expression Regulation, Neoplastic*
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Glioblastoma / therapy
  • Humans
  • Mice
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Multigene Family*
  • Neoplasm Proteins / biosynthesis*
  • Neoplasm Proteins / genetics
  • RNA, Neoplasm / biosynthesis*
  • RNA, Neoplasm / genetics

Substances

  • MicroRNAs
  • Neoplasm Proteins
  • RNA, Neoplasm