NFATC2 modulates radiation toxicity in dermal fibroblasts from patients with severe side-effects of radiotherapy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA646692 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12235500_1.fastq.gz | Fastqsanger.gz | |||
| SRR12235500_2.fastq.gz | Fastqsanger.gz | |||
| SRR12235477_1.fastq.gz | Fastqsanger.gz | |||
| SRR12235477_2.fastq.gz | Fastqsanger.gz | |||
| SRR12235478_1.fastq.gz | Fastqsanger.gz |
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Project description:Although it is well established that 5 to 15% of radiotherapy patients exhibit severe side-effects in healthy tissue, the cellular and molecular mechanisms involved are still poorly known, and the link between cellular and tissue radiosensitivity is still debated. We here studied fibroblasts from normal skin of patients with severe sequels of radiotherapy in order to examine if specific basal cell activities might be involved in susceptibility to side-effects. When compared to control cells, patient fibroblasts exhibited higher radiosensitivity and defects in DNA double strand breaks (DSB) repair and 8-oxoGuanines, abasic sites and glycol damaged base repair. Transcriptome profiling of dermal fibroblast cell strains 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 one of the most differentially expressed genes. This transcription factor involved in immune responses was found poorly expressed at transcript and protein level in patient cells, whereas the NFATC2 gene region was hypermethylated. Furthermore, NFATC2 expression correlated to the cell survival after irradiation. Finally, we observed that the silencing of NFATC2 in normal cells by RNA interference leads to increased cellular radiosensivity and defects in DNA DSB repair. This study demonstrates that patients with clinical hypersensitivity also exhibit intrinsic cellular radiosensitivity in normal skin cells. It further reveals a new role for NFATC2 as a potential regulator of the cellular sensitivity to ionizing radiations.
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Project description: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.
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Project description:The majority of patients tolerate radiotherapy well, but some of them suffer from severe side effects. To find genes possibly predictive for radiosensitivity, mRNA profiles were generated before and 6 h after in vitro irradiation with 5 Gy. We analyzed lymphocytes from four head and neck and eight breast cancer patients with strong acute radiation toxicity and from 12 matching normal reacting patients in a blind study. In peripheral blood lymphocytes of all patients, 153 genes were identified which were statistically significantly altered by a fold change of more than 50% by irradiation. Pathway analysis revealed genes involved in p53 signalling, cell cycle control and apoptosis in response to radiation in primary lymphocytes. In these cells, a set of 67 radiation-induced genes was identified capable of differentiating between severe radiosensitive and normal reacting patients. More than one third of such classifying genes belong to the group of apoptosis or cell cycle regulating genes. Total RNA obtained from lymphocytes of cancer patients with strong acute radiation toxicity and from matching normal reacting patients were compared 6 hours after in vitro irradiation with 5 Gy.
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