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

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• 5-15% of radiotherapy patients experience severe side effects in non-cancerous tissues.
• The molecular mechanisms underlying normal tissue radiosensitivity and patient susceptibility remain poorly understood.
• Links between cellular and tissue radiosensitivity are debated.

Purpose of the Study:

• Investigate basal cell activities in fibroblasts from radiotherapy patients with severe side effects.
• Determine if intrinsic cellular radiosensitivity in normal tissues contributes to clinical hypersensitivity.
• Identify molecular mechanisms and genes associated with differential radiosensitivity.

Main Methods:

• Studied dermal fibroblasts from radiotherapy patients with severe side effects and healthy controls.
• Assessed cellular radiosensitivity and DNA repair capacity.
• Performed transcriptome profiling to identify deregulated genes.
• Utilized RNA interference to silence NFATC2 expression in normal cells.

Main Results:

• Patient fibroblasts displayed higher radiosensitivity and DNA repair defects compared to controls.
• Transcriptome analysis revealed 540 deregulated genes in patients, with Nuclear Factor of activated T cells 2 (NFATC2) being the most significant.
• NFATC2 was underexpressed at transcript and protein levels, with hypermethylation of its gene region.
• NFATC2 expression correlated with cell survival post-irradiation, and its silencing in normal cells increased radiosensitivity and DNA repair defects.

Conclusions:

• Patients with clinical radiotherapy hypersensitivity exhibit intrinsic cellular radiosensitivity in normal skin cells.
• NFATC2 plays a significant role in regulating cellular sensitivity to ionizing radiation.
• NFATC2 is a potential predictive biomarker for radiotherapy-induced side effects.