Department of Radiation Oncology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, TX 75390, USA.
BMC Genomics. 2013 Jun 1;14:372. doi: 10.1186/1471-2164-14-372.
Ionizing radiation composed of accelerated ions of high atomic number (Z) and energy (HZE) deposits energy and creates damage in cells in a discrete manner as compared to the random deposition of energy and damage seen with low energy radiations such as γ- or x-rays. Such radiations can be highly effective at cell killing, transformation, and oncogenesis, all of which are concerns for the manned space program and for the burgeoning field of HZE particle radiotherapy for cancer. Furthermore, there are differences in the extent to which cells or tissues respond to such exposures that may be unrelated to absorbed dose. Therefore, we asked whether the energy deposition patterns produced by different radiation types would cause different molecular responses. We performed transcriptome profiling using human bronchial epithelial cells (HBECs) after exposure to γ-rays and to two different HZE particles (28Si and 56Fe) with different energy transfer properties to characterize the molecular response to HZE particles and γ-rays as a function of dose, energy deposition pattern, and time post-irradiation.
Clonogenic assay indicated that the relative biological effectiveness (RBE) for 56Fe was 3.91 and for 28Si was 1.38 at 34% cell survival. Unsupervised clustering analysis of gene expression segregated samples according to the radiation species followed by the time after irradiation, whereas dose was not a significant parameter for segregation of radiation response. While a subset of genes associated with p53-signaling, such as CDKN1A, TRIM22 and BTG2 showed very similar responses to all radiation qualities, distinct expression changes were associated with the different radiation species. Gene enrichment analysis categorized the differentially expressed genes into functional groups related to cell death and cell cycle regulation for all radiation types, while gene pathway analysis revealed that the pro-inflammatory Acute Phase Response Signaling was specifically induced after HZE particle irradiation. A 73 gene signature capable of predicting with 96% accuracy the radiation species to which cells were exposed, was developed.
These data suggest that the molecular response to the radiation species used here is a function of the energy deposition characteristics of the radiation species. This novel molecular response to HZE particles may have implications for radiotherapy including particle selection for therapy and risk for second cancers, risk for cancers from diagnostic radiation exposures, as well as NASA's efforts to develop more accurate lung cancer risk estimates for astronaut safety. Lastly, irrespective of the source of radiation, the gene expression changes observed set the stage for functional studies of initiation or progression of radiation-induced lung carcinogenesis.
与 γ 射线或 X 射线等低能辐射随机沉积能量和造成损伤不同，由高速、高原子序数（Z）的离子组成的电离辐射以离散的方式在细胞中沉积能量并造成损伤。此类辐射在杀伤细胞、引发转化和致癌方面非常有效，这些都是载人航天计划和新兴的 HZE 粒子癌症放射治疗领域所关注的问题。此外，细胞或组织对这些辐射的反应程度可能存在差异，而这种差异与吸收剂量无关。因此，我们想知道不同类型的辐射产生的能量沉积模式是否会导致不同的分子反应。我们使用人类支气管上皮细胞（HBEC）进行了转录组谱分析，这些细胞在暴露于 γ 射线和两种具有不同能量转移特性的不同 HZE 粒子（28Si 和 56Fe）后，我们对 HZE 粒子和 γ 射线的分子反应进行了特征描述，其特征是剂量、能量沉积模式和辐照后时间。
集落形成实验表明，56Fe 的相对生物效能（RBE）为 3.91，28Si 的 RBE 为 1.38，细胞存活率为 34%。基因表达的无监督聚类分析根据辐射种类对样本进行了分类，然后根据辐照后的时间进行分类，而剂量并不是辐射反应分类的重要参数。虽然与 p53 信号相关的一组基因，如 CDKN1A、TRIM22 和 BTG2 对所有辐射质量都表现出非常相似的反应，但不同的辐射种类与明显不同的表达变化相关。基因富集分析将差异表达基因分为与所有辐射类型的细胞死亡和细胞周期调节相关的功能组，而基因途径分析表明，促炎急性期反应信号在 HZE 粒子照射后被特异性诱导。开发了一种能够以 96%的准确率预测细胞暴露的辐射种类的 73 个基因特征。
这些数据表明，这里使用的辐射种类的分子反应是辐射种类的能量沉积特性的函数。这种对 HZE 粒子的新型分子反应可能对放射治疗具有重要意义，包括治疗中粒子的选择和二次癌症风险、诊断性辐射暴露的癌症风险，以及 NASA 为了更准确地估计宇航员肺癌风险而做出的努力。最后，无论辐射源如何，观察到的基因表达变化为辐射诱导的肺癌发生的起始或进展的功能研究奠定了基础。
