Mechanical compression induces VEGFA overexpression in breast cancer via DNMT3A-dependent miR-9 downregulation

Cell Death Dis. 2017 Mar 2;8(3):e2646. doi: 10.1038/cddis.2017.73.

Abstract

Tumor growth generates mechanical compression, which may trigger mechanotransduction in cancer and stromal cells and promote tumor progression. However, very little is known about how compression stimulates signal transduction and contributes to tumor progression. In the present study, we demonstrated that compression enhances a tumor progression phenotype using an in vitro compression model, and validated the results from the in vitro model with high- and low-compressed breast cancer tissues. Mechanical compression induced miR-9 downregulation by DNMT3A-dependent promoter methylation in the MDA-MB-231 and BT-474 breast cancer cell lines and in cancer-associated fibroblasts. The overexpression of miR-9 target genes (LAMC2, ITGA6, and EIF4E) was induced by miR-9 downregulation, which eventually enhanced vascular endothelial growth factors production. Demethylation and decompression could reverse compression-induced miR-9 downregulation and following overexpression of miR-9 target genes and VEGFA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • DNA Methylation / genetics
  • Disease Progression
  • Down-Regulation / genetics*
  • Female
  • Fibroblasts / pathology
  • Gene Expression Regulation, Neoplastic / genetics
  • Humans
  • MCF-7 Cells
  • Mechanotransduction, Cellular / genetics
  • MicroRNAs / genetics*
  • Promoter Regions, Genetic / genetics
  • Signal Transduction / genetics
  • Vascular Endothelial Growth Factor A / genetics*

Substances

  • MIRN92 microRNA, human
  • MicroRNAs
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A