Abstract
BackgroundRNA editing by adenosine deaminases acting on RNA (ADARs) converts adenosines to inosines (A-to-I) in RNA, that alters gene expression and generates protein diversity. Dysregulation of A-to-I editing has been found associated with a number of nervous system diseases. However, the role of ADAR3, a brain specific high expression adenosine deaminase, in gliomas has rarely been investigated. In this study we illuminated the clinical significance and molecular features of ADAR3 in patients with glioma.Methods309 glioma samples from Chinese Glioma Genome Atlas were enrolled into this study. In validation sets, 601 glioma samples in TCGA, 410 glioma samples in REMBRANDT and 258 glioma samples in GSE16011 were obtained. Relationships between ADAR3 expression and prognosis-related genomic alteration, outcome and gene ontology analysis were investigated. Moreover, the characteristic of GRIA2Q607R editing in gliomas has been investigated. Graphpad Prism 5.0, SPSS 16.0 and R language were used to perform statistical analysis and graphical work.ResultsADAR3 expression was down regulated along with glioma grade progression in CGGA dataset. ADAR3 was characteristically highly expressed in neural subtype and IDH1/2 mutant preference. Moreover, high expression of ADAR3 predicted a better prognosis in lower-grade glioma (LGG) patients and multivariate analysis suggested ADAR3 expression was an independent prognostic indicator. The results of the three other validation datasets showed similar findings. Bioinformatics analyses suggested that ADAR3 may play a role in the malignant transformation of glioma cells by affecting cell proliferation, angiogenesis or cell adhesion. Furthermore, the editing level of GRIA2Q607R was significantly correlated with ADAR3 expression.ConclusionsOur study demonstrated the clinical and molecular characterization of ADAR3 in glioma development and progression. ADAR3 expression was negatively associated with tumor malignant in the overall glioma patients. And it was a favorable independent prognostic indicator of LGG patients. ADAR3 appeared to act as a tumor suppressor in glioma cells. Therefore, ADAR3 represented a potential therapeutic target and useful prognostic factor for glioma patients.
Highlights
RNA editing by adenosine deaminases acting on RNA (ADARs) converts adenosines to inosines (A-to-I) in RNA, that alters gene expression and generates protein diversity
ADAR3 expression is down regulated along with glioma grade progression and shows a subtype preference To get an overview of adenosine deaminase domain containing proteins status in gliomas, we firstly investigated the mRNA expression of these proteins in patients
We compared the mRNA expression of ADAR1, ADAR2 and ADAR3 in patients with different World Health Organization (WHO) grades (II, III and IV) based Chinese Glioma Genome Atlas (CGGA) RNA sequencing (RNAseq)
Summary
RNA editing by adenosine deaminases acting on RNA (ADARs) converts adenosines to inosines (A-to-I) in RNA, that alters gene expression and generates protein diversity. In the 2016 WHO classification of central nervous system (CNS) tumors, classification of diffuse gliomas (WHO Grade II-IV) has fundamentally changed: for the first time, a large subset of these tumors is defined based on IDH1 or IDH2 mutation and co-deletion of chromosomal arms 1p and 19q [4]. This breaks with the principle of diagnosis based entirely on phenotypic by incorporating genotypic parameters into the classification of CNS tumor entities [4]. The exploit of novel and reliable biomarkers for the prediction of gliomas may further help to elucidate the molecular mechanism of glioma development and progression
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