Hypermethylation of Secreted Frizzled Related Protein 1 gene promoter in different astrocytoma grades

Abstract

AimTo identify the involvement of Secreted Frizzled Related Protein 1 (SFRP1) promoter hypermethylation in different malignancy grades of astrocytoma and assess its association with beta-catenin, lymphoid-enhancer factor 1, and T-cell factor 1.MethodsTwenty-six astrocytoma samples were collected from 2008-2015. Promoter hypermethylation was evaluated by methylation-specific polymerase-chain-reaction and protein expression by immunohistochemistry and stereological analysis. The staining intensity was scored by comparing immunoreactivity with normal tissue and by using 10% and 50% cut-offs.ResultsSFRP1 promoter methylation was found in 32% of astrocytomas. The number of hypermethylated samples increased in higher astrocytoma grades and was the highest in glioblastoma (P = 0.042 compared to other astrocytoma grades). There was 45.8% of samples with the lack of or weak expression of SFRP1 protein and 29.2% with strong expression. Samples with methylated promoter expressed significantly less SFRP1 than samples with unmethylated promoter (P = 0.031). Beta-catenin expression levels were elevated. Yet, glioblastomas with unmethylated SFRP1 promoter had significantly less beta-catenin (P = 0.033). Strong expression of lymphoid-enhancer factor 1 was associated to higher astrocytoma grades (P = 0.006).ConclusionSFRP1 gene was epigenetically silenced in glioblastomas when compared to low astrocytoma grades, which may suggest that the lack of its protein is involved in astrocytoma progression.

DNA methylation analysis with methylation‐sensitive high‐resolution melting (MS‐HRM) reveals gene panel for glioma characteristics

“…In this study, patients’ age ranged between 16 and 83 years of age, and higher methylation levels of two genes, namely SFRP1 and INA , were observed in older patients, which confirmed our previous observation, 26 indicating a more frequent occurrence of SFRP1 26 and RUNX3 27,28 promoter methylation in older CNS tumor patients. In turn, lack of association between age and SFRP1 methylation level was proved by Chang 57 and Kafka, 58 while no correlation for MGMT in the analysis of 58 anaplastic astrocytomas was reported by Bell et al 59 …”

Enhancing α-secretase Processing for Alzheimer’s Disease—A View on SFRP1

“…Dysregulation of SFRP1 gene expression is better known in the context of cancer, and SFRP1-promoter hypermethylation and suppression of expression has been associated with several different cancer types [110]. Of particular relevance to the brain are glioma [111] and astrocytoma [112]. Less is known about how SFRP1 expression is upregulated.…”

“…ADAM10 is the major source of human epidermal growth factor receptor 2 (HER2) ectodomain shedding activity in HER2-overexpressing breast cancer cells [137,138], and is known to promote cancer cell migration [39,41], invasiveness [42] and metastasis [40] in several contexts of cancer progression, as well as in brain glioma [139]. SFRP1 is negatively associated with cancer development and progression, and hypermethylation of SFRP1 promoter and transcription suppression [110] has been demonstrated for brain cancers of glial origin, such as glioma [140] and astrocytoma [112]. In this regard, SFRP1 s tumor suppression activity likely also has much to do with its inhibition of Wnt signaling.…”

COXIBs and 2,5-dimethylcelecoxib counteract the hyperactivated Wnt/β-catenin pathway and COX-2/PGE2/EP4 signaling in glioblastoma cells

“…One of the most critical oncogenic drivers of GBM is the Wnt/β-catenin pathway [ 7 ]. As we and others have previously shown, hyperactivation of this signaling pathway is mainly caused by promoter methylation of its inhibitors [ 8 – 10 ]. Without the protective role of its natural antagonists, Wnt pathway is hyperactivated, contributing to the maintenance of GBM cells stemness, invasiveness, and angiogenesis, as well as chemio- and radioresistance [ 7 ].…”