Identification of aberrant promoter methylation ofEDNRBgene in esophageal squamous cell carcinoma

Abstract

Epigenetic silencing of tumor suppressor genes is a major contributor to neoplastic transformation and is an area of intense research. The purpose of the present study was to identify the epigenetic changes in esophageal squamous cell carcinoma (ESCC). Methylation-sensitive arbitrarily primed polymerase chain reaction analysis was used on 21 matched ESCC tumors and adjacent normal tissues. Through this screen we identified a frequently methylated fragment that showed a high homology to the 5' CpG island of endothelin receptor type B (EDNRB) gene. The methylation status of the EDNRB gene was then detected by bisulfite sequencing and the levels of EDNRB mRNA were detected by quantitative real-time polymerase chain reaction (PCR). In addition, the effects of a methylation inhibitor 5-aza-2'-deoxycytidine on EDNRB mRNA expression was determined in cells of an ESCC cell lines. Hypermethylation of the 5' CpG island of EDNRB was found in 5 out of 21 (23.8%) primary tumors. Real-time PCR analysis demonstrated that EDNRB mRNA expression was significantly reduced in tumors showing high promoter methylation compared with paired normal tissues, whereas there is no significant difference between other paired samples. In addition, treatment of ESCC cell line with 5-aza-2'-deoxycytidine led to reexpression of the EDNRB transcript, which is correlated with the reversal of the methylation status of EDNRB promoter. In conclusion, promoter hypermethylation of EDNRB gene, which is associated with the loss of EDNRB mRNA expression, may play a role in the development of ESCC.

Hypermethylation of EDNRB promoter contributes to the risk of colorectal cancer

“…During the development of tumor, EDNRB gene transcription is downregulated by promoter hypermethylated, and consequently alters the ET1 signaling pathway [27]. Disruption in the ET1 signaling pathway has been shown to be involved in a variety of human tumor proliferation, angiogenesis, and metastasis [28-30]. EDNRB gene silencing by promoter hypermethylation has been reported in a variety of tumors such as leukemia, oral cancer, skin cancer, head and neck cancer, melanoma, renal cell carcinoma, bladder cancer, and prostate cancer [12-19].…”

Quantitative analysis of promoter methylation of the EDNRB gene in gastric cancer

“…Treatment with 5-aza-2 0 -deoxycytidine (5-Aza-CdR), which is a DNA demethylation agent [15], induces the expression of EDNRB in T24 cancer cells [14]. Silencing of EDNRB expression caused by promoter hypermethylation has also been shown in nasopharyngeal carcinoma, prostate cancer, melanoma, lung cancer, and esophageal carcinoma [16][17][18][19][20]. The high frequency of promoter hypermethylation suggests that downregulation of the EDNRB gene may be involved in human tumorigenesis.…”

Endothelin B receptor expression correlates with tumour angiogenesis and prognosis in oesophageal squamous cell carcinoma

“…A study has also shown that a dual receptor antagonist inhibited migration of human oesophageal cancer cells in vitro (Jiao et al , 2007). Furthermore, a recent study has identified aberrant promoter methylation of EDNRB gene, which encodes ETBR in humans, in OSCC (Zhao et al , 2009). Although these studies have suggested a potential role of ETBR in OSCC, little is known about its clinical importance.…”