TMEFF2 Promoter Hypermethylation Is an Unfavorable Prognostic Marker in Gliomas

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 if TMEFF2 methylation can be a prognostic marker in adult diffuse gliomas. Methods: In this study, we investigated TMEFF2 expression in surgical tissue samples of gliomas. 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 through analyzing a cohort dataset from TCGA. Results: Immunohistochemistry analysis of 75 paired glioma tumor and peritumoral tissues proved that glioma tumor tissue expressed TMEFF2 at levels that were lower than those of peritumoral tissues (P<0.001). The methylation level of the TMEFF2 promoter was higher in glioblastoma cells than it was in SVG p12 cells (P<0.001). Inhibition of methylation reduced TMEFF2 methylation and improved 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 gliomas harboring combined IDH1/ATRX/TP53 mutations was linked to low levels of TMEFF2 methylation. Survival analysis confirmed that low levels of TMEFF2 methylation are associated with a good prognosis in glioma patients. Conclusions: Our results suggest that TMEFF2 DNA methylation might be associated with glioma tumor progression and could serve as a valuable prognostic marker of adult diffuse gliomas.