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首页> 外文期刊>BMC Medical Genomics >Global gene expression analyses of bystander and alpha particle irradiated normal human lung fibroblasts: Synchronous and differential responses
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Global gene expression analyses of bystander and alpha particle irradiated normal human lung fibroblasts: Synchronous and differential responses

机译：旁观者和alpha粒子照射的正常人肺成纤维细胞的全局基因表达分析：同步和差异反应

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Background The existence of a radiation bystander effect, in which non-irradiated cells respond to signals from irradiated cells, is now well established. It raises concerns for the interpretation of risks arising from exposure to low doses of ionizing radiation. However, the regulatory mechanisms involved in the bystander response have not been well elucidated. To provide insight into the signaling pathways responding in bystanders, we have measured global gene expression four hours after bystander and direct alpha particle exposure of primary human lung fibroblasts. Results Although common p53-regulated radiation response genes like CDKN1A were expressed at elevated levels in the directly exposed cultures, they showed little or no change in the bystanders. In contrast, genes regulated by NFκB, such as PTGS2 (cyclooxygenase-2), IL8 and BCL2A1 , responded nearly identically in bystander and irradiated cells. This trend was substantiated by gene ontology and pathway analyses of the microarray data, which suggest that bystander cells mount a full NFκB response, but a muted or partial p53 response. In time-course analyses, quantitative real-time PCR measurements of CDKN1A showed the expected 4-hour peak of expression in irradiated but not bystander cells. In contrast, PTGS2, IL8 and BCL2A1 responded with two waves of expression in both bystander and directly irradiated cells, one peaking at half an hour and the other between four and six hours after irradiation. Conclusion Two major transcriptional hubs that regulate the direct response to ionizing radiation are also implicated in regulation of the bystander response, but to dramatically different degrees. While activation of the p53 response pathway is minimal in bystander cells, the NFκB response is virtually identical in irradiated and bystander cells. This alteration in the balance of signaling is likely to lead to different outcomes in irradiated cells and their bystanders, perhaps leading to greater survival of bystanders and increased risk from any long-term damage they have sustained.
机译：背景技术现在已经很好地确立了辐射旁观者效应的存在，其中未辐射的细胞响应来自辐射的细胞的信号。它引起了人们对低剂量电离辐射暴露引起的风险解释的关注。但是，有关旁观者响应的调节机制尚未得到很好的阐明。为了提供对旁观者反应的信号通路的深入了解，我们在旁观者和直接暴露于原代人肺成纤维细胞的阿尔法粒子后四小时测量了全球基因表达。结果尽管直接暴露于培养物中的普通p53调控的放射反应基因（如CDKN1A）以升高的水平表达，但旁观者几乎没有变化。相比之下，由NFκB调控的基因，例如PTGS2（环氧合酶-2），IL8和BCL2A1，在旁观者和受照细胞中的反应几乎相同。这种趋势已通过基因本体论和微阵列数据的途径分析得到了证实，这表明旁观者细胞会出现完整的NFκB反应，而产生p53突变或部分沉默。在时程分析中，对CDKN1A进行定量实时PCR测量显示，辐照后的旁观者细胞中预期的4小时表达高峰。相比之下，PTGS2，IL8和BCL2A1在旁观者和直接照射的细胞中均以两次表达波响应，一个波在半小时达到峰值，另一个在照射后四到六个小时达到峰值。结论调节对电离辐射的直接响应的两个主要转录中心也参与了旁观者响应的调节，但程度不同。尽管旁观者细胞中p53应答途径的激活作用极小，但辐照细胞和旁观者细胞中的NFκB应答实际上是相同的。信号平衡的这种改变很可能导致受辐照细胞及其旁观者的结局不同，也许会导致旁观者的存活率更高，并承受遭受任何长期损害的风险增加。

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