Role of exosomal miRNAs in brain metastasis affected by radiotherapy.

Zihuang Li,Meili Chen,Rencui Quan,Hongli Yang,Ling Ye

doi:10.1515/tnsci-2020-0163

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.

Highlights

Brain metastases are the most common intracranial malignant tumors, and their primary foci typically include lung cancer (20–56%), breast cancer (5–20%), and melanoma (7–16%), as well as colorectal cancer and renal cell carcinoma [1,2]
For the global analysis of the miRNA signature derived from plasma exosomes of brain metastasis, ten clinical plasma exosomes were collected for sequence analysis, including five brain metastasis samples before radiotherapy (M-BR) and five after radiotherapy (M-AR) (Table 1)
The result of Gene ontology (GO) enrichment analysis showed that the significantly differentially expressed miRNAs in plasma exosomes were associated with metabolic processes and transcription regulator activity, which were associated with cancer-associated pathways, and may play an important role in brain metastasis

Summary

Introduction

Brain metastases are the most common intracranial malignant tumors, and their primary foci typically include lung cancer (20–56%), breast cancer (5–20%), and melanoma (7–16%), as well as colorectal cancer and renal cell carcinoma [1,2]. Brain metastasis occurs because of the proliferation of cells. Once brain metastasis occurred in patients with cancer, they induce various central nervous system (CNS) symptoms that severely reduce the quality of life of patients, resulting in poor prognosis and high mortality. To solve the problem of poor prognosis in patients with brain metastasis, we need to understand the disease complexity at the molecular level. Some hypotheses have been proposed to explain the unique metastasis patterns of different primary cancers, including the importance of “seeds” (cancer cells) and “soil” (microenvironment of receiving organs) or changes in circulation patterns between primary and metastatic tumors. It is important to understand the unique biological sensitivity of each tumor and the molecular differences occurring because of the corresponding treatment of brain metastasis. The CNS is protected by various functional barriers, including the blood–brain barrier

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