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Rosmarinic acid alleviates radiation-induced pulmonary fibrosis by downregulating tRNA N7-Methylguanosine modification-regulated fibroblast to myofibroblast transition through the exosomes pathway [Ribo-Seq]

ABSTRACT: Radiation-induced pulmonary fibrosis (RIPF) is a common complication after radiotherapy in thoracic cancer patients, and there is a lack of effective treatment methods. The aim of this study was to explore the protective effect of rosmarinic acid (RA) on RIPF in mice as well as the underlying mechanism.We found that RA exerted an antifibrotic effect on lung tissues of RIPF mouse models and inhibited the progression of FMT through exosomes derived from lung epithelial cells. Mechanistically, RA reduced the transcription and translation efficiency of SPHK1 in lung fibroblasts by decreasing the tRNA N7-methylguanosine modification and downregulating the expression of tRNAs in lung epithelial cell-derived exosomes after irradiation, as well as inhibiting the interaction of SPHK1 with the NAT10 protein in fibroblasts. Furthermore, exosomes derived from irradiated lung epithelial cells after RA intervention decreased the acetylation and cytoplasmic translocation of PFKFB3, suppressing the FMT process triggered by glycolysis, and ultimately decelerating the progression of RIPF.

ORGANISM(S): Mus musculus

PROVIDER: GSE249532 | GEO | 2024/09/02

REPOSITORIES: GEO

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Project description:Background: Rosmarinic acid (RA), a natural phenolic acid, exhibits promising anti-cancer properties. The abnormal expression of microRNA (miRNA) regulates the gene expression and plays a role as an oncogenic or tumor suppressor in TNBC. However, the biological role of RA in miR-30a-5p on BCL2L11 during MDA-MB-231 induced breast cancer stem-like cells (BCSCs) progression and its regulatory mechanism have not been elucidated. Objective: To investigate whether RA inhibited the silencing effect of miR-30a-5p on the BCL2L11 gene and promoted apoptosis in BCSCs. Materials and Methods: We assessed the migration, colony formation, proliferation, cell cycle, and apoptosis of BCSCs after RA treatment using the wound-healing assay, colony formation assay, CCK-8 assay, and flow cytometry, respectively. The expression of mRNA and protein levels of BCL-2, Bax, BCL2L11, and P53 genes in BCSCs after RA treatment was obtained by real-time polymerase chain reaction and Western blot. Differential miRNA expression in BCSCs was analyzed by high-throughput sequencing. Targetscan was utilized to predict the targets of miR-30a-5p. The dual luciferase reporter system was used for validation of the miR-30a-5p target. Results: Wound-healing assay, colony formation assay, CCK-8 assay, and cell cycle assay results showed that RA inhibited migration, colony formation and viability of BCSCs, and cell cycle arrest in the G0-G1 phase. At the highest dose of RA, we noticed cell atrophy, while the arrest rate at 100 μg/mL RA surpassed that at 200 μg/mL RA. Apoptotic cells appeared early (Membrane Associated Protein V FITC+, PI-) or late (Membrane Associated Protein V FITC+, PI+) upon administration of 200 μg/mL RA, Using high-throughput sequencing to compare the differences in miRNA expression, we detected down-regulation of miR-30a-5p expression, and the results of dual luciferase reporter gene analysis indicated that BCL2L11 was a direct target of miR-30a-5p. Conclusion: RA inhibited the silencing effect of miR-30a-5p on the BCL2L11 gene and enhanced apoptosis in BCSCs. Keywords Apoptosis; miR-30a-5p; BCSCs; Rosmarinic acid; Triple-negative breast cancer

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Rosmarinic acid alleviates radiation-induced pulmonary fibrosis by downregulating tRNA N7-Methylguanosine modification-regulated fibroblast to myofibroblast transition through the exosomes pathway [Ribo-Seq]

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