Egr-1 activation by cancer-derived extracellular vesicles promotes endothelial cell migration via ERK1/2 and JNK signaling pathways

PLoS One. 2014 Dec 12;9(12):e115170. doi: 10.1371/journal.pone.0115170. eCollection 2014.

Abstract

Various mammalian cells, including cancer cells, shed extracellular vesicles (EVs), also known as exosomes and microvesicles, into surrounding tissues. These EVs play roles in tumor growth and metastasis by promoting angiogenesis. However, the detailed mechanism of how cancer-derived EVs elicit endothelial cell activation remains unknown. Here, we provide evidence that early growth response-1 (Egr-1) activation in endothelial cells is involved in the angiogenic activity of colorectal cancer cell-derived EVs. Both RNA interference-mediated downregulation of Egr-1 and ERK1/2 or JNK inhibitor significantly blocked EV-mediated Egr-1 activation and endothelial cell migration. Furthermore, lipid raft-mediated endocytosis inhibitor effectively blocked endothelial Egr-1 activation and migration induced by cancer-derived EVs. Our results suggest that Egr-1 activation in endothelial cells may be a key mechanism involved in the angiogenic activity of cancer-derived EVs. These findings will improve our understanding regarding the proangiogenic activities of EVs in diverse pathological conditions including cancer, cardiovascular diseases, and neurodegenerative diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement / physiology*
  • Early Growth Response Protein 1 / metabolism*
  • Endothelial Cells / metabolism*
  • Extracellular Vesicles / metabolism*
  • HCT116 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • MAP Kinase Signaling System*
  • Membrane Microdomains / metabolism
  • Membrane Microdomains / pathology
  • Mice
  • Neoplasms / blood supply
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Neovascularization, Pathologic / metabolism
  • RNA Interference

Substances

  • EGR1 protein, human
  • Early Growth Response Protein 1

Grants and funding

This work was supported by Mid-career Researcher Program through NRF grant funded by the MEST (No. 2014023004), BK21 Plus (10Z20130012243) funded by the Ministry of Education, Korea, and the National Research Foundation of Korea (2011-0030049). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.