Discovery of G protein-coupled receptor 158 as a potential glioma biomarker


Year:

Session type:

Theme:

Ying Zhang1,Ningning Li1,Kastytis Sidlauskas1,Shu An1,Matthew Ellis1,Angela Richart-Londt1,Jessica Broni1,Joanne Lau1,Sebastian Brandner1
1University College London

Abstract

Background

As reported previously, concomitant deletion of p53 and Pten in mouse subventricular zone gives rise to glioma, while codeletion of p53 and Rb generates primitive neuroectodermal tumours (PNET). These experimental gliomas and PNETs exhibit significant differences in tumour proliferation and differentiation, which can be used as a tool to identify biomarkers for tumour malignance.

Method

We performed mRNA and microRNA expression array of murine gliomas and PNETs. Differentially expressed miRNAs were validated using quantitative RT-PCR. Direct binding of microRNA with its target RNAs was confirmed using a double pull-down assay, which hybrids Ago2 immunoprecipitation with biotin affinity pull-down. We then analysed the biomarker expression on human glioma samples from two cohorts, TCGA (n=430) and our institution (NHNN, n=93). 

Results

The analysis of microRNA profiles identified a significant up-regulation of miR-449a in PNET when compared with gliomas. Among putative targets of miR-449a, G protein-coupled receptor 158 (GPR158) was identified as one of the key genes with a potential role in tumour malignance. Using double pull-down assay, we confirmed that GPR158 was a direct target of miR-449a. Subsequently, we confirmed the inverse correlation of miR-449a and GPR158 expression in human frozen glioma samples.Next we analysed GPR158 expression levels in different types of gliomas, and we found that GPR158 expression level was highest in central nervous system (CNS) and oligodendroglioma (IDH mutant and 1p/19q codeletion), followed by IDH mutant astrocytomas and it was lowest in primary glioblastomas. We also found that patients with gliomas expressing higher levels of GPR158 survived longer. Interestingly, patients with GBM expressing higher GPR158 showed a better response to chemotherapy. However, higher GPR158 expression led to shorter survival when GBM patients received hormone treatment. 

Conclusion

In this study, we discovered the direct interaction between miR-449a and GPR158. Our data suggested that GPR158 was a potential diagnostic and prognostic marker in gliomas.