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Role of exosomal miRNAs in brain metastasis affected by radiotherapy.

ABSTRACT: In oncogenesis and development of malignant tumor, microRNAs (miRNAs) regulate the complex gene expression associated with the tumor pathogenesis. Currently, only few studies have been conducted to identify miRNAs and the potential pathways involved in the pathogenesis of brain metastasis in patients who underwent radiotherapy, especially miRNAs in the plasma exosomes. Therefore, this study is aimed to use small RNA analysis to identify miRNAs and their potential target genes in plasma exosomes during the initiation and development of brain metastasis in patients who underwent radiotherapy. Using high-throughput sequencing technologies, we identified 35 differentially expressed miRNAs in patients with brain metastasis who had undergone radiotherapy. In annotation of miRNA targets, gene ontology enrichment analysis revealed that the targets of the differentially expressed miRNAs were significantly enriched in the regulation of cellular processes. Kyoto Encyclopedia of Genes and Genomes revealed that most of the miRNA targets were cancer-related, including genes involved in the mitogen-activated protein kinase signaling pathway, cancer-related pathways, phosphatidylinositol 3-kinase-protein kinase B signaling pathway, microtubule-associated protein kinase signaling pathway, Ras signaling pathway, regulation of the actin cytoskeleton, and axon guidance. In conclusion, this study provides a new perspective to understand the possible function of these miRNAs in the pathogenesis of brain metastasis. This was the first time that a pilot study identified plasma exosomal miRNAs in five patients with brain metastasis before and after radiotherapy. This study is the beginning; more specimen and further research are needed to explore the functional role of specific miRNAs and their potential as therapeutic targets for brain metastasis.

SUBMITTER: Li Z

PROVIDER: S-EPMC8012736 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCirculating exosomes from prostate cancer (PCa) patients undergoing radiotherapy are attractive candidate biomarkers for monitoring treatment response. Multiple workflows for isolation and content characterization of exosomes in biofluids have been attempted. We report a protocol to isolate and characterize exosomal miRNAs content and assess radiation-induced changes.MethodsIn this pilot study, we performed targeted exosomal miRNA profiling of 25 serum samples obtained from PCa patients with intermediate- and high-risk disease treated with curative radiotherapy (RT), and controls. Post-treatment blood samples were collected at least 28 days after radiation therapy as a paired follow-up sample. The complete workflow consisted of two phases: I) filtration and polyethylene glycol salt precipitation phase which enriched particles below 200 nm in size followed by characterization using electron microscopy, and II) flow cytometry. Finally, miRNA expression analysis between untreated and treated patient samples was performed using RNA extraction kit, and qRT-PCR.ResultsIn our preliminary data, 1 ml of serum from PCa patients showed higher exosomal concentration (3.68E+10) compared to controls (6.07E+08). The overall expression of exosomes after RT was found to be higher compared to untreated samples; the median value changed from 3.68E+10 to 5.40E+10; p = 0.52. Using electron microscopy, we were able to visualize cup-shaped vesicles with morphology and size compatible with exosomes. The bead-based flow cytometry showed positivity for exosomal tetraspanins surface markers CD63 and CD9. All five miRNAs (hsa-let-7a-5p, hsa-miR-141-3p, hsa-miR-145-5p, hsa-miR-21-5p, hsa-miR-99b-5p) have been identified in exosomes. Despite overall changes in hsa-let-7a-5p expression after radiation, the difference was significant only in the high-risk group (p = 0.037). In addition, the radiation response to hsa-miR-21-5p was elevated in the high-risk group compared to the intermediate group (p = 0.036).ConclusionsHerewith, we demonstrated a protocol for isolation of serum exosomes and exosomal miRNA amplification. The recovery of exosomal miRNAs and their differential expression after radiation treatment suggests promising biomarker potential that requires further investigation in larger patient cohorts.

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Role of exosomal miRNAs in brain metastasis affected by radiotherapy.

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