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高能粒子辐射相关的正常小鼠致癌转化:探讨癌基因激活与癌基因成瘾之间的联系。

High Energy Particle Radiation-associated Oncogenic Transformation in Normal Mice: Insight into the Connection between Activation of Oncotargets and Oncogene Addiction.

机构信息

Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Stephenson Cancer Center, Oklahoma City, OK, USA.

出版信息

Sci Rep. 2016 Nov 23;6:37623. doi: 10.1038/srep37623.

Abstract

Concerns on high-energy particle radiation-induced tumorigenic transformation of normal tissue in astronauts, and in cancer patients undergoing radiotherapy, emphasizes the significance of elucidating the mechanisms involved in radiogenic transformation processes. Mostly used genetically modified or tumor-prone models are less reliable in determining human health risk in space or protracted post-treatment normal tissue toxicity. Here, in wild type C57BL/6 mice, we related the deregulation of distinctive set of tissue-specific oncotargets in major organs upon Fe (600 MeV/amu; 0.5 Gy/min; 0.8 Gy) particle radiation and compared the response with low LET γ-radiation (Cs; 0.5 Gy/min; 2 Gy). One of the novel findings is the 'tissue-independent' activation of TAL2 upon high-energy radiation, and thus qualifies TAL2 as a potential biomarker for particle and other qualities of radiation. Heightened expression of TAL2 gene transcript, which sustained over four weeks post-irradiation foster the concept of oncogene addiction signaling in radiogenic transformation. The positive/negative expression of other selected oncotargets that expresses tissue-dependent manner indicated their role as a secondary driving force that addresses the diversity of tissue-dependent characteristics of tumorigenesis. This study, while reporting novel findings on radiogenic transformation of normal tissue when exposed to particle radiation, it also provides a platform for further investigation into different radiation quality, LET and dose/dose rate effect in healthy organs.

摘要

宇航员和接受放射治疗的癌症患者高能粒子辐射引起的正常组织肿瘤转化问题,强调了阐明放射转化过程中涉及的机制的重要性。大多数使用的遗传修饰或易患肿瘤的模型在确定太空或长期治疗后正常组织毒性中的人类健康风险方面不太可靠。在这里,在野生型 C57BL/6 小鼠中,我们研究了主要器官中一组独特的组织特异性致癌靶点在 Fe(600 MeV/amu;0.5 Gy/min;0.8 Gy)粒子辐射下的失调情况,并将其与低 LET γ 辐射(Cs;0.5 Gy/min;2 Gy)进行了比较。新发现之一是高能辐射后 TAL2 的“组织非依赖性”激活,因此 TAL2 有资格成为粒子和其他辐射质量的潜在生物标志物。TAL2 基因转录物的表达水平升高,在照射后持续四周以上,这支持了放射转化中致癌基因成瘾信号的概念。其他选定的以组织依赖性方式表达的致癌靶点的阳性/阴性表达表明它们作为次要驱动力的作用,解决了肿瘤发生的组织依赖性特征的多样性。本研究在报告了暴露于粒子辐射时正常组织放射转化的新发现的同时,也为进一步研究不同的辐射质量、LET 以及健康器官中的剂量/剂量率效应提供了一个平台。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bfc6/5120307/601eab4a453e/srep37623-f1.jpg

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