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NFATC2 Modulates Radiation Sensitivity in Dermal Fibroblasts From Patients With Severe Side Effects of Radiotherapy

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-ir...

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Autores principales: Dulong, Joshua, Kouakou, Clara, Mesloub, Yasmina, Rorteau, Julie, Moratille, Sandra, Chevalier, Fabien P., Vinasco-Sandoval, Tatiana, Martin, Michèle T., Lamartine, Jérôme
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772431/
https://www.ncbi.nlm.nih.gov/pubmed/33392083
http://dx.doi.org/10.3389/fonc.2020.589168
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author Dulong, Joshua
Kouakou, Clara
Mesloub, Yasmina
Rorteau, Julie
Moratille, Sandra
Chevalier, Fabien P.
Vinasco-Sandoval, Tatiana
Martin, Michèle T.
Lamartine, Jérôme
author_facet Dulong, Joshua
Kouakou, Clara
Mesloub, Yasmina
Rorteau, Julie
Moratille, Sandra
Chevalier, Fabien P.
Vinasco-Sandoval, Tatiana
Martin, Michèle T.
Lamartine, Jérôme
author_sort Dulong, Joshua
collection PubMed
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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spelling pubmed-77724312020-12-31 NFATC2 Modulates Radiation Sensitivity in Dermal Fibroblasts From Patients With Severe Side Effects of Radiotherapy Dulong, Joshua Kouakou, Clara Mesloub, Yasmina Rorteau, Julie Moratille, Sandra Chevalier, Fabien P. Vinasco-Sandoval, Tatiana Martin, Michèle T. Lamartine, Jérôme Front Oncol Oncology 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. Frontiers Media S.A. 2020-12-16 /pmc/articles/PMC7772431/ /pubmed/33392083 http://dx.doi.org/10.3389/fonc.2020.589168 Text en Copyright © 2020 Dulong, Kouakou, Mesloub, Rorteau, Moratille, Chevalier, Vinasco-Sandoval, Martin and Lamartine http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Dulong, Joshua
Kouakou, Clara
Mesloub, Yasmina
Rorteau, Julie
Moratille, Sandra
Chevalier, Fabien P.
Vinasco-Sandoval, Tatiana
Martin, Michèle T.
Lamartine, Jérôme
NFATC2 Modulates Radiation Sensitivity in Dermal Fibroblasts From Patients With Severe Side Effects of Radiotherapy
title NFATC2 Modulates Radiation Sensitivity in Dermal Fibroblasts From Patients With Severe Side Effects of Radiotherapy
title_full NFATC2 Modulates Radiation Sensitivity in Dermal Fibroblasts From Patients With Severe Side Effects of Radiotherapy
title_fullStr NFATC2 Modulates Radiation Sensitivity in Dermal Fibroblasts From Patients With Severe Side Effects of Radiotherapy
title_full_unstemmed NFATC2 Modulates Radiation Sensitivity in Dermal Fibroblasts From Patients With Severe Side Effects of Radiotherapy
title_short NFATC2 Modulates Radiation Sensitivity in Dermal Fibroblasts From Patients With Severe Side Effects of Radiotherapy
title_sort nfatc2 modulates radiation sensitivity in dermal fibroblasts from patients with severe side effects of radiotherapy
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772431/
https://www.ncbi.nlm.nih.gov/pubmed/33392083
http://dx.doi.org/10.3389/fonc.2020.589168
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