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FRA1 (FOSL1) Suppresses Neoplastic Transformation and Modulates Radiation Responses via Transcriptional Control of Mitogenic and Stress-Responsive Networks

ABSTRACT: Purpose: FOS-like antigen 1 (FRA1), encoded by FOSL1, is an inducible subunit of the AP-1 transcription factor complex and regulates gene expression in response to proliferative and environmental cues. Although FRA1 has been linked to cancer progression, its role in early transformation and radiation responses remains unclear. Methods: CRISPR-engineered human CGL1 cells—a hybrid of HeLa and normal fibroblasts—were used to evaluate the impact of FRA1 overexpression and knockout on neoplastic transformation. Transformation frequency, clonogenic survival, DNA damage recognition and repair, and cell cycle distribution were assessed following irradiation. Transcriptomic profiling was performed under baseline and serum-stimulated conditions. Results: FRA1 loss markedly increased both spontaneous and radiation-induced transformation frequency, while overexpression suppressed transformation under both conditions. FRA1-deficient cells were sensitized to radiation-induced cell killing, despite intact DNA damage recognition and repair. In contrast, FRA1 overexpression promoted G2/M accumulation post-irradiation, suggesting enhanced checkpoint activation. Transcriptomic profiling revealed that FRA1 remodels AP-1 complex composition and functions as a transcriptional repressor of mitogen- and stress-responsive genes. FRA1-mediated repression was observed across gene networks involved in extracellular matrix remodeling, hypoxia signaling, inflammation, and proliferation, under both baseline and serum-stimulated conditions. Conclusion: These findings establish FRA1 as a key modulator of neoplastic transformation and radiation response, acting primarily through transcriptional repression of pro-tumorigenic signaling pathways.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307991 | GEO | 2025/09/15

REPOSITORIES: GEO

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Project description:Background: Ionizing Radiation (IR) is a known pro-inflammatory agent and in the process of development of biomarkers for radiation biodosimetry a chronic inflammatory disease condition could act as a confounding factor. Hence, it is important to develop radiation biodosimetry that can distinguish between IR-induced inflammatory responses and pre-existing disease. In this study, we compared the gene expression response of a genetically modified mouse model of inflammatory bowel disease (Il10-/-) with that of a normal wild-type mouse to potentially develop transcriptomic based biodosimetry markers for individual susceptibility to radiation. Results: Wild-type (WT) and Il10-/- mice were exposed to whole body irradiation of 7Gy (LD50/30 for IL10-/-) X-rays. Gene expression responses were studied using high throughput whole genome microarrays in peripheral blood after 24h post-irradiation. Analysis resulted in identification of 1962 and 1844 genes differentially expressed (p < 0.001, FDR < 10%) after radiation exposure in Il10-/- and WT mice respectively. A set of 155 genes were also identified as differentially expressing between WT and Il10-/- mice at the baseline pre-irradiation level. Gene ontology analysis revealed that the baseline differentially expressing genes (155) were mainly involved in Inflammatory response, Glutathione metabolism and fibrosis. Analysis of radiation responsive genes revealed commonality of immune function genes between WT and Il10-/- mice. Gene ontology analysis revealed that innate immune response and p53 signaling processes were strongly associated with up-regulated genes whereas, B-cell development process was found to be significant amongst downregulated genes in response to radiation in the two genotypes. However, specific immune response pathways like MHC class I antigen presentation and response to viral/bacterial infection were particularly associated with radiation responsive genes of Il10-/- mice but not with WT mice. Further analysis of activation status of specific canonical pathways and upstream regulators using IPA-prediction tool revealed significant difference in the activation status of T-cell and hormone mediated signaling as well as regulators of inflammation between WT and Il10-/- after irradiation.

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FRA1 (FOSL1) Suppresses Neoplastic Transformation and Modulates Radiation Responses via Transcriptional Control of Mitogenic and Stress-Responsive Networks

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