Abstract
Ciliary neurotrophic factor receptor α subunit (CNTFRα) and CNTF play important roles in neuron survival, glial differentiation and brain tumor growth. However, the molecular mechanisms of CNTFRα regulation and its clinical significance in glioma remain largely unknown. Here, we found CNTFRα was overexpressed in lower grade gliomas (LGG) compared with glioblastoma (GBM) and normal brain specimens in TCGA datasets and in an independent cohort. Bioinformatics analysis revealed a CpG shore of the CNTFRα gene regulated its mRNA expression in TCGA datasets. This observation was further validated with clinical specimens and functionally verified using demethylating agents. Additionally, we observed that independent of IDH mutation status, methylation of CNTFRα was significantly correlated with down-regulated CNTFRα gene expression and longer LGG patient survival. Interestingly, combination of CNTFRα methylation and IDH mutation significantly (p < 0.05) improved the prognostic prediction in LGG patients. Furthermore, the role of CNTFRα in glioma proliferation and apoptosis through the PI3K/AKT pathways was demonstrated by supplementation with exogenous CNTF in vitro and siRNA knockdown in vivo. Our study demonstrated that hypomethylation leading to CNTFRα up-regulation, together with autocrine expression of CNTF, was involved in glioma growth regulation. Importantly, DNA methylation of CNTFRα might serve as a potential epigenetic theranostic target for LGG patients.
Highlights
Glioma is one of the most common primary brain tumors
Bioinformatics analysis of TCGA glioma datasets revealed that Ciliary neurotrophic factor receptor α subunit (CNTFRα) mRNA level was significantly higher in lower grade gliomas (LGG) (n = 530) than that in normal brain tissues (n = 5) (Fig. 1A, p < 0.05, fold change = 0.42)
The overexpression of CNTFRα in LGG (n = 28) was further confirmed at the protein level by western blot analysis of our clinical samples compared with normal brain tissues (n = 5, p < 0.05, Fig. 1B and C)
Summary
Glioma is one of the most common primary brain tumors. Despite surgical resection and chemo-radiotherapy, the prognosis of glioblastoma (GBM) patients remains dismal. Aberrant growth factors and receptors such as EGF/EGFR2, IGF/IGFR3, PDGF/PDGFR4, and CNTF/CNTFR5, become constantly active and contribute to glioma progression. These growth factors have been the focus as molecular markers and therapeutic targets for gliomas. The objective of the present study was to investigate the role of CNTF/CNTFRα and its regulation in gliomas. To this end, the expression of CNTFRα in gliomas was analyzed in both the TCGA dataset and in an independent clinical sample collection. CNTFRα expression was compared between LGG, GBM, and normal brain specimens, and the role of DNA methylation in the regulation of CNTFRα expression was investigated. Our results demonstrated a relationship between the DNA methylation of a CpG island shore located in the first intron of CNTFRα, experimental tumor growth and poorer survival in LGG patients
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