Exosomal miR-130b-3p targets SIK1 to inhibit medulloblastoma tumorigenesis

Saihua Huang,Lan Yang,Jinrong Fu,Ping Xue,Lijuan Liu,Xiao Han,Caiyan Zhang,Hao Li,Xiang Wang,Yufeng Zhou

doi:10.1038/s41419-020-2621-y

Saihua Huang, Lan Yang + Show 8 more

Open Access

https://doi.org/10.1038/s41419-020-2621-y

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Abstract

Exosomes are an important carrier for cell communication. miRNAs in exosomes are potential biomarkers and therapeutic targets in different types of cancer. However, the role of exosomal miRNAs in medulloblastoma (MB) patients is largely unknown. In this study, we reported that there was a higher level of miR-130b-3p in exosomes derived from MB patient plasma compared with exosomes from healthy control plasma. Exosomes from MB patient plasma could transfer miR-130b-3p to an MB cell line and played suppressor roles for cell proliferation. miR-130b-3p suppressed MB tumorigenesis by targeting a previously unknown target, serine/threonine-protein kinase 1 (SIK1), through the p53 signaling pathways. In addition, we found an unreported role of SIK1 in promoting MB tumor growth and an SIK1 inhibitor could inhibit MB cell proliferation. This research provides new insight into the molecular mechanism of MB and may provide a new therapeutic strategy for MB treatment.

Highlights

Medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for 20−30% of children with central nervous system malignancies[1], and the peak incidence is between 3 and 4 years and 8 and 9 years of age[2]
To identify differentially expressed exosomal miRNA in MB, we previously analyzed the miRNA expression profiles of exosomes derived from MB patient plasma by RNA-seq (GSE123376, submitted in other draft), and found miR-130b-3p was highly expressed in exosomes from MB patient plasma compared with healthy controls (n = 3, fold-change >1.5) (Supplementary Fig. S1)
Exosomes have been studied for several years, the biological roles of exosomal miRNAs are just beginning to be investigated. miRNAs serve as important intercellular communication tools, as they are transferred between cells via exosomes and influence the phenotypes of their recipient cells[26,27,28]

Summary

Introduction

Medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for 20−30% of children with central nervous system malignancies[1], and the peak incidence is between 3 and 4 years and 8 and 9 years of age[2]. Exosomes are secreted by all living cells, and are small membrane vesicles of 50−150 nm in diameter containing microRNAs (miRNAs), protein, lipids, DNA and mRNA8,9. MiRNAs are highly conserved, singlestranded RNA molecules of 19−24 nucleotides long[11]. They regulate genes by binding to the 3′ untranslated region (3′UTR) of target messenger RNA12,13. Exosomal miRNAs are emerging as novel regulators of cellular function[14,15,16]. Exosomal miRNAs moving from cancer cells to endothelial cells could promote tumor metastasis[17]. Exosomal miRNAs secreted from immune cells were shown to exert an antiproliferative effect on tumor cells[14]. MiRNAs in exosomes are potential biomarkers and therapeutic targets in different types of cancer

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