Abstract
Although it is well established that 5 to 15% of radiotherapy patients exhibit severe side-effects in non-cancerous tissues, the molecular mechanisms involved are still poorly known, and the links between cellular and tissue radiosensitivity are still debated. We here studied fibroblasts from non-irradiated skin of patients with severe sequelae of radiotherapy, to determine whether specific basal cell activities might be involved in susceptibility to side-effects in normal tissues. Compared to control cells, patient fibroblasts exhibited higher radiosensitivity together with defects in DNA repair. Transcriptome profiling of dermal fibroblasts from 16 radiotherapy patients with severe side-effects and 8 healthy individuals identified 540 genes specifically deregulated in the patients. Nuclear factor of activated T cells 2 (NFATC2) was the most differentially expressed gene, poorly expressed at both transcript and protein level, whereas the NFATC2 gene region was hypermethylated. Furthermore, NFATC2 expression correlated with cell survival after irradiation. Finally, silencing NFATC2 in normal cells by RNA interference led to increased cellular radiosensitivity and defects in DNA repair. This study demonstrates that patients with clinical hypersensitivity also exhibit intrinsic cellular radiosensitivity in their normal skin cells. It further reveals a new role for NFATC2 as a potential regulator of cellular sensitivity to ionizing radiation.
Highlights
Radiosensitivity is the relative sensitivity of cells, tissues, organs, and organisms to the injurious effects of ionizing radiations
To study patient cell DNA repair ability, we first performed immunofluorescence against gH2AX and 53BP1, two early markers of DNA double-strand breaks (DSB), in four control and four radiosensitive cell strains after 2 Gy irradiation
Among the most differentially expressed genes between control and patient fibroblasts identified by our RNA sequencing approach, we focused on Nuclear factor of activated T cells 2 (NFATC2), which encodes a transcription factor initially described in T-cell activation and involved in numerous cellular functions such as apoptosis and the cell cycle [21]
Summary
Radiosensitivity is the relative sensitivity of cells, tissues, organs, and organisms to the injurious effects of ionizing radiations. This notion includes very different outcomes according to the scale at which it is analyzed. NFATC2 Modulates Fibroblast Radiation Sensitivity whereas the majority of the population exposed to the same dose show no or only mild effects This is obvious in the context of radiotherapy (RT), the main source of human exposure to high-dose ionizing radiation, where 5–15% of patients exhibit severe side-effects in irradiated normal tissues [1, 2], including fibrosis [3], necrosis, and sometimes radioinduced secondary cancers [4, 5]. Other authors reported no difference in dermal fibroblast radiosensitivity between radiosensitive and radio-tolerant individuals [14, 15]
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