HCMV-encoded miR-UL112-3p promotes glioblastoma progression via tumour suppressor candidate 3

Qing Liang,Kejia Wang,Bin Wang,Qiliang Cai

doi:10.1038/srep44705

Abstract

Glioblastoma (GBM) is the most prevalent and lethal type of primary malignant brain tumour. Recent studies suggest that the discovery of human cytomegalovirus (HCMV)-encoded microRNAs (miRNAs) might play a role in the pathogenesis of diseases, including GBM. In this study, we aimed to analyse the expression and function of HCMV-encoded miRNAs in GBM. We found that miR-UL112-3p expression was significantly elevated in GBM, and its expression levels were highly associated with glioma size, differentiation, WHO stage and the overall and disease-free survival of patients. The overexpression of miR-UL112-3p in the GBM cells promoted cell proliferation, clone formation, migration and invasion. In contrast, the down-regulation of miR-UL112-3p exerted an inverse effects. Tumour suppressor candidate 3 (TUSC3), a potential target gene of miR-UL112-3p, was inversely correlated with miR-UL112-3p expression in GBM tissues and cell lines. Furthermore, we demonstrated that TUSC3 was directly regulated by miR-UL112-3p, and the ectopic expression of TUSC3 reversed the effects of miR-UL112-3p on GBM progression via the AKT signalling pathway. Taken together, these findings collectively demonstrate that miR-UL112-3p exerts its oncogene function by directly targeting TUSC3 in GBM, indicating a potential novel therapeutic target for GBM.

Highlights

Glioblastoma (GBM) is the most aggressive and lethal brain tumour that is a potential hazard to human health, with a median survival of 12–14 months[1,2]
All of the HCMV-positive glioma specimens were confirmed by Immediate Early 86 protein (IE86) immunohistochemistry staining (Supplementary Figure S1)
We detected the expression of miR-UL112-3p in 20 pairs of HCMV-positive GBM tissues and matched adjacent normal tissues from GBM patients who received surgery at our hospital, and a heatmap analysis of the HCMV miRNomes was undertaken (Fig. 1A)

Summary

Introduction

Glioblastoma (GBM) is the most aggressive and lethal brain tumour that is a potential hazard to human health, with a median survival of 12–14 months[1,2] It is characterised by highly invasive behaviour and infiltrative proliferation, which account for its high mortality[3]. MicroRNAs (miRNAs) are short, single-stranded RNA molecules that function in the regulation of gene expression via direct binding to the target mRNAs (including 3′untranslated regions (3′UTRs), 5′untranslated regions (5′UTR) and coding region)[7]. They are involved in the regulation of various biological processes, including cell proliferation, differentiation, apoptosis, metastasis, and angiogenesis[8]. Our findings demonstrated that HCMV-encoded miR-UL112-3p might act as a tumour regulator by directly targeting TUSC3 in GBM

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