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Title: Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells

Abstract

Highlights: • Oncogenic H-ras stimulates emission of extracellular vesicles containing double-stranded DNA. • Vesicle-associated extracellular DNA contains mutant N-ras sequences. • Vesicles mediate intercellular transfer of mutant H-ras DNA to normal fibroblasts where it remains for several weeks. • Fibroblasts exposed to vesicles containing H-ras DNA exhibit increased proliferation. - Abstract: Cell free DNA is often regarded as a source of genetic cancer biomarkers, but the related mechanisms of DNA release, composition and biological activity remain unclear. Here we show that rat epithelial cell transformation by the human H-ras oncogene leads to an increase in production of small, exosomal-like extracellular vesicles by viable cancer cells. These EVs contain chromatin-associated double-stranded DNA fragments covering the entire host genome, including full-length H-ras. Oncogenic N-ras and SV40LT sequences were also found in EVs emitted from spontaneous mouse brain tumor cells. Disruption of acidic sphingomyelinase and the p53/Rb pathway did not block emission of EV-related oncogenic DNA. Exposure of non-transformed RAT-1 cells to EVs containing mutant H-ras DNA led to the uptake and retention of this material for an extended (30 days) but transient period of time, and stimulated cell proliferation. Thus, our study suggests that H-ras-mediated transformation stimulates vesicular emission of this histone-boundmore » oncogene, which may interact with non-transformed cells.« less

Authors:
;  [1];  [2]; ;  [1];  [1]
  1. Montreal Children’s Hospital, Research Institute of McGill University Health Centre, McGill University, Montreal, Quebec (Canada)
  2. McGill University and Genome Quebec Innovation Centre, Montreal, Quebec (Canada)
Publication Date:
OSTI Identifier:
22416720
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 451; Journal Issue: 2; Other Information: Copyright (c) 2014 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; BIOLOGICAL MARKERS; BRAIN; CELL PROLIFERATION; CHROMATIN; DNA; EV RANGE; FIBROBLASTS; HUMAN POPULATIONS; MICE; MUTANTS; NEOPLASMS; ONCOGENES; RATS; RETENTION; TRANSIENTS; TUMOR CELLS; UPTAKE

Citation Formats

Lee, Tae Hoon, Chennakrishnaiah, Shilpa, Audemard, Eric, Montermini, Laura, Meehan, Brian, and Rak, Janusz, E-mail: janusz.rak@mcgill.ca. Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells. United States: N. p., 2014. Web. doi:10.1016/J.BBRC.2014.07.109.
Lee, Tae Hoon, Chennakrishnaiah, Shilpa, Audemard, Eric, Montermini, Laura, Meehan, Brian, & Rak, Janusz, E-mail: janusz.rak@mcgill.ca. Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells. United States. doi:10.1016/J.BBRC.2014.07.109.
Lee, Tae Hoon, Chennakrishnaiah, Shilpa, Audemard, Eric, Montermini, Laura, Meehan, Brian, and Rak, Janusz, E-mail: janusz.rak@mcgill.ca. Fri . "Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells". United States. doi:10.1016/J.BBRC.2014.07.109.
@article{osti_22416720,
title = {Oncogenic ras-driven cancer cell vesiculation leads to emission of double-stranded DNA capable of interacting with target cells},
author = {Lee, Tae Hoon and Chennakrishnaiah, Shilpa and Audemard, Eric and Montermini, Laura and Meehan, Brian and Rak, Janusz, E-mail: janusz.rak@mcgill.ca},
abstractNote = {Highlights: • Oncogenic H-ras stimulates emission of extracellular vesicles containing double-stranded DNA. • Vesicle-associated extracellular DNA contains mutant N-ras sequences. • Vesicles mediate intercellular transfer of mutant H-ras DNA to normal fibroblasts where it remains for several weeks. • Fibroblasts exposed to vesicles containing H-ras DNA exhibit increased proliferation. - Abstract: Cell free DNA is often regarded as a source of genetic cancer biomarkers, but the related mechanisms of DNA release, composition and biological activity remain unclear. Here we show that rat epithelial cell transformation by the human H-ras oncogene leads to an increase in production of small, exosomal-like extracellular vesicles by viable cancer cells. These EVs contain chromatin-associated double-stranded DNA fragments covering the entire host genome, including full-length H-ras. Oncogenic N-ras and SV40LT sequences were also found in EVs emitted from spontaneous mouse brain tumor cells. Disruption of acidic sphingomyelinase and the p53/Rb pathway did not block emission of EV-related oncogenic DNA. Exposure of non-transformed RAT-1 cells to EVs containing mutant H-ras DNA led to the uptake and retention of this material for an extended (30 days) but transient period of time, and stimulated cell proliferation. Thus, our study suggests that H-ras-mediated transformation stimulates vesicular emission of this histone-bound oncogene, which may interact with non-transformed cells.},
doi = {10.1016/J.BBRC.2014.07.109},
journal = {Biochemical and Biophysical Research Communications},
number = 2,
volume = 451,
place = {United States},
year = {Fri Aug 22 00:00:00 EDT 2014},
month = {Fri Aug 22 00:00:00 EDT 2014}
}