Hypoxic Glioma Cell-Secreted Exosomal miR-301a Activates Wnt/β-catenin Signaling and Promotes Radiation Resistance by Targeting TCEAL7

Mol Ther. 2019 Nov 6;27(11):1939-1949. doi: 10.1016/j.ymthe.2019.07.011. Epub 2019 Jul 22.

Abstract

Recent evidence suggests that microRNAs (miRNAs) can be released to the extracellular microenvironment and mediate cell-cell communication through exosomes. The aim of this study was to identify exosomal miR-301a (exo-miR-301a) involved in glioblastoma (GBM) radioresistance and reveal the possible mechanisms. The exo-miR-301a specifically secreted by hypoxic GBM cells could transfer to corresponding normoxia-cultured cells and promote radiation resistance. Hypoxic exo-miR-301a directly targeted TCEAL7 genes, which were identified as a tumor suppressor in GBM malignancy and actively repressed its' expression in normoxic glioma cells. Our studies indicated that TCEAL7 negatively regulated the Wnt/β-catenin pathway by blocking β-catenin translocation from cytoplasm to nucleus. Interestingly, we clarified that the Wnt/β-catenin signaling was activated by miR-301a and TCEAL7 mediated the important procession. The exo-miR-301a was involved in the resistance to radiotherapy, and the effects would be reversed by miR-301a inhibition or TCEAL7 overexpression to regulate the Wnt/β-catenin axis. Here we show that exo-miR-301a, which is characteristically expressed and secreted by hypoxic glioma cells, is a potent regulator of Wnt/β-catenin and then depresses radiation sensitivity through targeting anti-oncogene TCEAL7. The newly identified exo-miR-301a/TCEAL7-signaling axis could present a novel target for cellular resistance to cancer therapeutic radiation in GBM patients.

Keywords: Wnt/β-catenin; exosome; glioblastoma; hypoxia; miR-301a.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Cell Line, Tumor
  • Exosomes / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Glioma / genetics*
  • Glioma / metabolism*
  • Glioma / pathology
  • Glioma / radiotherapy
  • Humans
  • Hypoxia / genetics*
  • Hypoxia / metabolism*
  • MicroRNAs / genetics*
  • Nuclear Proteins / genetics*
  • Prognosis
  • RNA Interference
  • Radiation Tolerance / genetics
  • Wnt Signaling Pathway*

Substances

  • Biomarkers
  • MIRN301 microRNA, human
  • MicroRNAs
  • Nuclear Proteins
  • TCEAL7 protein, human