Jansen Jeannette, Vieten Patricia, Pagliari Francesca, Hanley Rachel, Marafioti Maria Grazia, Tirinato Luca, Seco Joao
Department of Biomedical Physics in Radiooncology, German Cancer Research Center, Heidelberg, Germany.
Department for Physics and Astronomy, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany.
Front Genet. 2021 Apr 28;12:597635. doi: 10.3389/fgene.2021.597635. eCollection 2021.
Whilst the impact of hypoxia and ionizing radiations on gene expression is well-understood, the interplay of these two effects is not. To better investigate this aspect at the gene level human bladder, brain, lung and prostate cancer cell lines were irradiated with photons (6 Gy, 6 MV LINAC) in hypoxic and normoxic conditions and prepared for the whole genome analysis at 72 h post-irradiation. The analysis was performed on the obtained 20,000 genes per cell line using PCA and hierarchical cluster algorithms to extract the most dominant genes altered by radiation and hypoxia. With the help of the introduced novel radiation-in-hypoxia and oxygen-impact profiles, it was possible to overcome cell line specific gene regulation patterns. Based on that, 37 genes were found to be consistently regulated over all studied cell lines. All DNA-repair related genes were down-regulated after irradiation, independently of the oxygen state. Cell cycle-dependent genes showed up-regulation consistent with an observed change in cell population in the S and G2/M phases of the cell cycle after irradiation. Genes behaving oppositely in their regulation behavior when changing the oxygen concentration and being irradiated, were immunoresponse and inflammation related genes. The novel analysis method, and by consequence, the results presented here have shown how it is important to consider the two effects together (oxygen and radiation) when analyzing gene response upon cancer radiation treatment. This approach might help to unrevel new gene patterns responsible for cancer radioresistance in patients.
虽然缺氧和电离辐射对基因表达的影响已得到充分理解，但这两种效应的相互作用却并非如此。为了在基因水平上更好地研究这一方面，在缺氧和常氧条件下，用光子（6 Gy，6 MV直线加速器）对人膀胱、脑、肺和前列腺癌细胞系进行照射，并在照射后72小时准备进行全基因组分析。使用主成分分析（PCA）和层次聚类算法对每个细胞系获得的20000个基因进行分析，以提取受辐射和缺氧影响而改变的最主要基因。借助引入的新型缺氧辐射和氧影响图谱，有可能克服细胞系特异性基因调控模式。基于此，发现37个基因在所有研究的细胞系中受到一致调控。所有与DNA修复相关的基因在照射后均下调，与氧状态无关。细胞周期依赖性基因表现出上调，这与照射后细胞周期S期和G2/M期细胞群体的观察变化一致。当改变氧浓度并进行照射时，其调控行为相反的基因是免疫反应和炎症相关基因。这种新的分析方法以及本文给出的结果表明，在分析癌症放射治疗后的基因反应时，将这两种效应（氧和辐射）一起考虑是多么重要。这种方法可能有助于揭示患者癌症放射抗性的新基因模式。
