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Biochem Biophys Res Commun. 2014 Aug 22;451(2):295-301. doi: 10.1016/j.bbrc.2014.07.109. Epub 2014 Jul 30.

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

Author information

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.
3
Montreal Children's Hospital, Research Institute of McGill University Health Centre, McGill University, Montreal, Quebec, Canada. Electronic address: janusz.rak@mcgill.ca.

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 (30days) 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.

KEYWORDS:

Chromatin; DNA; Extracellular vesicle; Oncogene; Ras; Sphingomyelinase

PMID:
25086355
DOI:
10.1016/j.bbrc.2014.07.109
[Indexed for MEDLINE]

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