Abstract
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.
Highlights
Cancer remains a major global health challenge, as it is estimated that the number of deaths caused by cancer might increase to over 13 million deaths per year in 2030 (World Health Organisation, 2021)
This manuscript aims to investigate the gene expression levels of different cancer cell lines [lung (H460), prostate(PC3), brain (H4), and bladder (T24)] after irradiation with 6 Gy photons in hypoxic and normoxic environment with a special focus given to DNA repair, cell cycle, inflammation and immune response genes by using a novel analysis method
A clear clustering of the four cell lines was visible, with H4 and T24 being separated from H460 and PC3
Summary
Cancer remains a major global health challenge, as it is estimated that the number of deaths caused by cancer might increase to over 13 million deaths per year in 2030 (World Health Organisation, 2021). It is known that cells surviving X-ray treatment show altered genetic expression levels especially related to DNA repair, cell cycle, inflammation and immune response (McKelvey et al, 2018) As these cells show an increased radioresistance, it is crucial to understand the effect of hypoxia in radiation treatment. This manuscript aims to investigate the gene expression levels of different cancer cell lines [lung (H460), prostate(PC3), brain (H4), and bladder (T24)] after irradiation with 6 Gy photons in hypoxic and normoxic environment with a special focus given to DNA repair, cell cycle, inflammation and immune response genes by using a novel analysis method. An oxygen level of 0.3% was set for hypoxic experiments, as levels below 1% O2 are usually considered hypoxic (McKeown, 2014). 0.3% was chosen to be in a clearly hypoxic regime while still allowing for the cells to proliferate (Carmeliet et al, 1998; Zheng et al, 2019)
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