Department of Biological Sciences, University of Lethbridge, 4401 University Drive, Lethbridge, Alberta, T1K 3M4 Canada.
Carcinogenesis. 2010 Oct;31(10):1882-8. doi: 10.1093/carcin/bgq119. Epub 2010 Jul 19.
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.
辐射诱导的旁观者效应（RIBE）是一种现象，即未暴露的细胞在相邻或附近的细胞受到电离辐射（IR）时表现出应激暴露的分子症状。最近的数据表明，RIBE 可能是由 microRNAs（miRNAs）介导的表观遗传现象，miRNAs 是一种靶向信使 RNA 转录本的翻译抑制的小调节分子。在这里，我们使用 miRNA 微阵列分析了三维人工组织经α粒子微束照射后旁观者组织中的 microRNAome 变化。我们的结果表明，IR 导致旁观者组织中 miRNA 表达的失调。我们报告说，主要的旁观者终点，包括细胞凋亡、细胞周期失调和 DNA 低甲基化，可能是由 miRNA 表达的改变介导的。具体而言，c-MYC 介导的 miR-17 家族上调与 E2F1 和 RB1 水平的降低有关，表明旁观者组织向增殖状态的转变，同时为即将到来的死亡信号使这些细胞做好准备。miR-29 家族的上调导致其靶基因 DNMT3a 和 MCL1 的水平降低，从而影响 DNA 甲基化和细胞凋亡。miR-16 的表达改变导致 BCL2 的表达改变，提示细胞凋亡的调节。因此，我们的数据清楚地表明，miRNAs 在晚期 RIBE 终点的表现中起着重要作用。总之，这项研究为理解 microRNAome 在 RIBE 中的作用以及开发新的 RIBE 生物标志物奠定了基础。
