Sidi Xie1,2, Yunxiao Zhang1,2, Tao Peng3, Jinglin Guo1,2, Yongfu Cao4, Jing Guo5, Xiaofeng Shi6, Yaqin Li7, Yawei Liu1,2, Songtao Qi8,9, Hai Wang10,11. 1. Department of Neurosurgery, Nanfang Glioma Center, Nanfang Hospital, Southern Medical University, Guangzhou North Road, Guangzhou, 510515, Guangdong, People's Republic of China. 2. Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China. 3. Department of Neurosurgery, First Hospital of Jilin University, Changchun, 130021, Jilin, People's Republic of China. 4. Department of Neurosurgery, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, Guangdong, People's Republic of China. 5. Epilepsy Center, Guangdong Sanjiu Brain Hospital, Guangzhou, 510000, Guangdong, People's Republic of China. 6. Department of Neurosurgery, Longgang Central Hospital of Shenzhen, Shenzhen, 518116, Guangdong, People's Republic of China. 7. The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, People's Republic of China. 8. Department of Neurosurgery, Nanfang Glioma Center, Nanfang Hospital, Southern Medical University, Guangzhou North Road, Guangzhou, 510515, Guangdong, People's Republic of China. qisongtaonfyy@126.com. 9. Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China. qisongtaonfyy@126.com. 10. Department of Neurosurgery, Nanfang Glioma Center, Nanfang Hospital, Southern Medical University, Guangzhou North Road, Guangzhou, 510515, Guangdong, People's Republic of China. shandongwanghai@163.com. 11. Laboratory for Precision Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, People's Republic of China. shandongwanghai@163.com.
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.
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 gliomapatients. 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.
Entities:
Keywords:
DNA methylation; Glioma; IDH1; Prognosis; TMEFF2
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