Journal Article

microRNAome changes in bystander three-dimensional human tissue models suggest priming of apoptotic pathways

Olga Kovalchuk, Franz J. Zemp, Jody N. Filkowski, Alvin M. Altamirano, Jennifer S. Dickey, Gloria Jenkins-Baker, Stephen A. Marino, David J. Brenner, William M. Bonner and Olga A. Sedelnikova

in Carcinogenesis

Volume 31, issue 10, pages 1882-1888
Published in print October 2010 | ISSN: 0143-3334
Published online July 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq119
microRNAome changes in bystander three-dimensional human tissue models suggest priming of apoptotic pathways

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The radiation-induced bystander effect (RIBE) is a phenomenon whereby unexposed cells exhibit molecular symptoms of stress exposure when adjacent or nearby cells are traversed by ionizing radiation (IR). Recent data suggest that RIBE may be epigenetically mediated by microRNAs (miRNAs), which are small regulatory molecules that target messenger RNA transcripts for translational inhibition. Here, we analyzed microRNAome changes in bystander tissues after α-particle microbeam irradiation of three-dimensional artificial human tissues using miRNA microarrays. Our results indicate that IR leads to a deregulation of miRNA expression in bystander tissues. We report that major bystander end points, including apoptosis, cell cycle deregulation and DNA hypomethylation, may be mediated by altered expression of miRNAs. Specifically, c-MYC-mediated upregulation of the miR-17 family was associated with decreased levels of E2F1 and RB1, suggesting a switch to a proliferative state in bystander tissues, while priming these cells for impending death signals. Upregulation of the miR-29 family resulted in decreased levels of its targets DNMT3a and MCL1, consequently affecting DNA methylation and apoptosis. Altered expression of miR-16 led to changes in expression of BCL2, suggesting modulation of apoptosis. Thus, our data clearly show that miRNAs play a profound role in the manifestation of late RIBE end points. In summary, this study creates a roadmap for understanding the role of microRNAome in RIBE and for developing novel RIBE biomarkers.

Journal Article.  5541 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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