Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, USA.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA, USA.
Carcinogenesis. 2020 Nov 13;41(11):1565-1575. doi: 10.1093/carcin/bgaa021.
Space radiation is characterized by high-linear energy transfer (LET) ionizing radiation. The relationships between the early biological effects of space radiation and the probability of cancer in humans are poorly understood. Bcl2 not only functions as a potent antiapoptotic molecule but also as an oncogenic protein that induces DNA replication stress. To test the role and mechanism of Bcl2 in high-LET space radiation-induced lung carcinogenesis, we created lung-targeting Bcl2 transgenic C57BL/6 mice using the CC10 promoter to drive Bcl2 expression selectively in lung tissues. Intriguingly, lung-targeting transgenic Bcl2 inhibits ribonucleotide reductase activity, reduces dNTP pool size and retards DNA replication fork progression in mouse bronchial epithelial cells. After exposure of mice to space radiation derived from 56iron, 28silicon or protons, the incidence of lung cancer was significantly higher in lung-targeting Bcl2 transgenic mice than in wild-type mice, indicating that Bcl2-induced DNA replication stress promotes lung carcinogenesis in response to space radiation. The findings provide some evidence for the relative effectiveness of space radiation and Bcl-2 at inducing lung cancer in mice.
空间辐射的特点是高线性能量转移（LET）电离辐射。人们对空间辐射的早期生物学效应与人类癌症发病率之间的关系知之甚少。Bcl2 不仅作为一种有效的抗凋亡分子发挥作用，而且还作为一种致癌蛋白，诱导 DNA 复制应激。为了测试 Bcl2 在高 LET 空间辐射诱导肺致癌中的作用和机制，我们使用 CC10 启动子创建了肺靶向 Bcl2 转基因 C57BL/6 小鼠，使 Bcl2 在肺组织中选择性表达。有趣的是，肺靶向转基因 Bcl2 抑制核昔酸还原酶活性，降低 dNTP 池大小，并延缓小鼠支气管上皮细胞中的 DNA 复制叉进展。在将小鼠暴露于源自 56Fe、28Si 或质子的空间辐射后，肺靶向 Bcl2 转基因小鼠的肺癌发病率明显高于野生型小鼠，表明 Bcl2 诱导的 DNA 复制应激促进了对空间辐射的肺癌发生。这些发现为空间辐射和 Bcl-2 在诱导小鼠肺癌方面的相对有效性提供了一些证据。
