Carcinogenesis Advance Access published online on March 7, 2007
Carcinogenesis, doi:10.1093/carcin/bgm053
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Role of epigenetic effectors in maintenance of the long-term persistent bystander effect in spleen in vivo
* Department of Biological Sciences, University of Lethbridge, Alberta, T1K 3M4, Canada
Department of Neuroscience, University of Lethbridge, Alberta, T1K 3M4, Canada
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079, USA
# Correspondence to: olga.kovalchuk{at}uleth.ca
Radiation therapy (RT) is a primary treatment modality for brain tumors, yet it has been linked to the increased incidence of secondary, post-RT cancers. These cancers are thought to be linked to indirect radiation-induced bystander effect. Bystander effect occurs when irradiated cells communicate damage to nearby, non-irradiated ‘bystander’ cells, ultimately contributing to genome destabilization in the non-exposed cells. Recent evidence suggests that bystander effect may be epigenetic in nature; however, characterization of epigenetic mechanisms involved in bystander effect generation and its long-term persistence has yet to be defined.
To investigate the possibility that localized X-ray-irradiation induces persistent bystander effects in distant tissue, we monitored the induction of epigenetic changes (i.e. alterations in DNA methylation, histone methylation and miRNA expression) in the rat spleen tissue 24 hours and 7 months after localized cranial exposure to 20Gy of X rays.
We found that localized cranial radiation exposure led to the induction of bystander effect in lead-shielded, distant spleen tissue. Specifically, this exposure caused the profound epigenetic dysregulation in the bystander spleen tissue which manifested as a significant loss of global DNA methylation, alterations in methylation of LINE 1 retrotransposable elements, and downregulation of DNA methyltransferases and methyl-binding protein MeCP2. Further, irradiation significantly altered expression of miR-194, a microRNA putatively targeting both DNMT3a and MeCP2. This study is the first to report conclusive evidence of the long-term persistence of bystander effects in radiation carcinogenesis target organ (spleen) upon localized distant exposure using the doses comparable to those used for clinical brain tumor treatments.
Two first authors contributed equally to the research. Received August 10, 2006; revised February 23, 2007; accepted March 2, 2007.
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