TMEFF2 promoter hypermethylation is an unfavorable prognostic marker in gliomas

Author:

Xie Sidi,Zhang Yunxiao,Peng Tao,Guo Jinglin,Cao Yongfu,Guo Jing,Shi Xiaofeng,Li Yaqin,Liu Yawei,Qi Songtao,Wang HaiORCID

Abstract

Abstract Background Transmembrane protein with EGF-like and two follistatin-like domains 2 (TMEFF2) is a transmembrane protein in the tomoregulin family. Little research has been performed to determine whether TMEFF2 methylation is a prognostic marker in adult diffuse gliomas. Methods In this study, we investigated TMEFF2 expression in surgical glioma tissue samples. In addition, we conducted bisulfite amplicon sequencing (BSAS) and methylation-specific PCR (MSP) to evaluate TMEFF2 methylation in glioblastoma (GBM) cells. Subsequently, we investigated the biological function of TMEFF2 in GBM cells. Moreover, we explored the prognostic significance of TMEFF2 in gliomas by analysing a cohort dataset from TCGA. Results Immunohistochemistry analysis of 75 paired glioma tumour and peritumoural tissues demonstrated that glioma tumour tissues expressed lower TMEFF2 levels than peritumoural tissues (P < 0.001). TMEFF2 promoter methylation levels were increased in glioblastoma cells compared with SVG p12 cells (P < 0.001). Inhibition of methylation reduced TMEFF2 methylation and increased its expression in LN229 and T98G cells (P < 0.05). Knockdown of TMEFF2 expression significantly promoted the proliferation of U87MG cells and primary GBM cells (P < 0.05). TMEFF2 methylation is negatively associated with IDH1, ATRX and TP53 mutations, and the subtype of glioma harbouring combined IDH1/ATRX/TP53 mutations was associated with low TMEFF2 methylation levels. Survival analysis confirmed that low TMEFF2 methylation levels are associated with good prognosis in glioma patients. Conclusions Our results suggest that TMEFF2 DNA methylation might be associated with glioma tumour progression and could serve as a valuable prognostic marker for adult diffuse gliomas.

Funder

National Natural Science Foundation of China

Guangdong Science and Technology Department

PLA Logistics Research Project of China

Key R&D Program of Guangdong Province

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Genetics,Oncology

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