VEGFA activates an epigenetic pathway upregulating ovarian cancer-initiating cells. Academic Article uri icon

Overview

abstract

  • The angiogenic factor, VEGFA, is a therapeutic target in ovarian cancer (OVCA). VEGFA can also stimulate stem-like cells in certain cancers, but mechanisms thereof are poorly understood. Here, we show that VEGFA mediates stem cell actions in primary human OVCA culture and OVCA lines via VEGFR2-dependent Src activation to upregulate Bmi1, tumor spheres, and ALDH1 activity. The VEGFA-mediated increase in spheres was abrogated by Src inhibition or SRC knockdown. VEGFA stimulated sphere formation only in the ALDH1+ subpopulation and increased OVCA-initiating cells and tumor formation in vivo through Bmi1. In contrast to its action in hemopoietic malignancies, DNA methyl transferase 3A (DNMT3A) appears to play a pro-oncogenic role in ovarian cancer. VEGFA-driven Src increased DNMT3A leading to miR-128-2 methylation and upregulation of Bmi1 to increase stem-like cells. SRC knockdown was rescued by antagomir to miR-128. DNMT3A knockdown prevented VEGFA-driven miR-128-2 loss, and the increase in Bmi1 and tumor spheres. Analysis of over 1,300 primary human OVCAs revealed an aggressive subset in which high VEGFA is associated with miR-128-2 loss. Thus, VEGFA stimulates OVCA stem-like cells through Src-DNMT3A-driven miR-128-2 methylation and Bmi1 upregulation.

publication date

  • March 1, 2017

Research

keywords

  • Epigenesis, Genetic
  • MicroRNAs
  • Neoplastic Stem Cells
  • Ovarian Neoplasms
  • Polycomb Repressive Complex 1
  • Vascular Endothelial Growth Factor A

Identity

PubMed Central ID

  • PMC5331266

Scopus Document Identifier

  • 85012273643

Digital Object Identifier (DOI)

  • 10.15252/emmm.201606840

PubMed ID

  • 28179359

Additional Document Info

volume

  • 9

issue

  • 3