Endoglin promoter hypermethylation identifies a field defect in human primary esophageal cancer

Abstract

Endoglin (ENG) is a 180-kDa transmembrane glycoprotein that functions as a component of the transforming growth factor-β receptor complex. Recently, ENG promoter hypermethylation was reported in several human cancers. We examined ENG promoter hypermethylation using real-time quantitative methylation-specific PCR in 260 human esophageal tissues. ENG hypermethylation showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) from normal esophagus (N) (p<0.01). Interestingly, ENG normalized methylation values were significantly higher in ESCC than in N (p<0.01) or EAC (p<0.01). ENG hypermethylation frequency was 46.2% in ESCC and 11.9% in N, but increased early and sequentially during EAC-associated neoplastic progression, to 13.3% in Barrett’s metaplasia (BE), 25% in dysplastic BE (D), and 26.9% in frank EAC. ENG hypermethylation was significantly higher in N from ESCC patients (mean = 0.0186) than in N from EAC patients (mean = 0.0117; p < 0.05). Treatment of KYSE220 ESCC cells with the demethylating agent, 5-aza-2′-deoxycytidine, reversed ENG methylation and reactivated ENG mRNA expression. We conclude that promoter hypermethylation of ENG is a frequent, tissue-specific event in human ESCC and exhibits a field defect with promising biomarker potential for the early detection of ESCC. In addition, ENG hypermethylation occurs in a subset of human EAC, and early during BE-associated esophageal neoplastic progression.

Matrix metalloproteinases and gastrointestinal cancers: Impacts of dietary antioxidants

“…Report suggested that H. pyroli infection induced promoter methylations of THBS1 and GATA-4 gene in the early stages of chronic gastritis and gastric cancer development [22] . Jin et al [23,24] reported the enhanced rate of promoter methylation of a transmembrane glycoprotein endoglin and Ras-related associated with diabetes gene in human ESCC. Also, TIMP-3 hypermethylation contributes to the downregulation TIMP-3 protein expression in ESCC and is associated with poor patient survival [25] .…”

Epigenetic modulation as a therapeutic approach for pulmonary arterial hypertension

“…Treatment with a demethylation agent restored the endoglin expression in carcinoma cell lines, suggesting the potential epigenetic regulation of the endoglin promoter. 68 Moreover, several miRNAs are known to target endoglin in endothelial cells or cardiac myocytes. In particular, miR-208a repressed endoglin expression in the heart, whereas miR-370 was negatively correlated with endoglin expression in endometrioid ovarian cancer cells.…”