Methylation of CLDN6, FBN2, RBP1, RBP4, TFPI2, and TMEFF2 in esophageal squamous cell carcinoma

Abstract

Abstract. In the development and progression of cancer, tumor suppressor genes may be silenced by mechanisms such as methylation. Thus the discovery of new genes silenced by methylation may uncover new tumor suppressor genes, and improve our understanding of cancer biology. In this study we investigated the methylation of 19 genes in esophageal squamous cell carcinoma. Methylation was measured in 10 of these genes in esophageal squamous cell carcinoma cell lines: CDH13, CLDN6, C16orf62, FBN2, FNBP1, ID4, RBP1, RBP4, TFPI2 and TMEFF2. To determine if there was a correlation between DNA methylation and gene silencing, each cell line was cultured with or without the demethylating drug 5-aza-2'-deoxycytidine (aza-dC). For 6 genes (CLDN6, FBN2, RBP1, RBP4, TFPI2 and TMEFF2) there was an association between reduction of methylation and increase in mRNA expression in the demethylated cell lines. The frequency of the methylation of these 6 genes in esophageal squamous cell carcinoma resection specimens was also investigated. All 6 genes showed more frequent methylation in the tumor than the matched proximal resection margin of uninvolved esophagus. There was a significant difference in the frequency of methylation and in the extent of the methylation between the cancer and the margin tissues for CLDN6, FBN2, TFPI2 and TMEFF2 (P=0.0007, P=0.0048 P=0.0002 and P<0.0001, respectively). This is the first report of gene silencing by methylation of CLDN6, FBN2, RBP4, TFPI2 and TMEFF2 in esophageal squamous cell carcinoma.

Three Epigenetic Biomarkers, GDF15, TMEFF2, and VIM, Accurately Predict Bladder Cancer from DNA-Based Analyses of Urine Samples

“…Both TMEFF2 (located at chromosome band 2q32.3, encoding a transmembrane protein with EGF-like domains and 2 follistatin-like domains 2, involved in cell proliferation control) and VIM (located at chromosome band 10p13, encoding the intermediate filament vimentin) have been previously found to be silenced through aberrant promoter methylation in esophageal, gastric, and colon cancer (34)(35)(36)(37)(38)(39)(40). Interestingly, a higher frequency of TMEFF2 promoter methylation in tumor tissue than in morphologically normal tumor-adjacent tissue has been reported for BlCa (41) in line with our results, although no association with grade or stage was apparent.…”

Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma

“…None of the nine genes have been previously reported to be methylated in RCC and, to the best of our knowledge, CCDC8, ATP5G2, KLHL35, CORO6, ZSCAN18 and SCUBE3 have not been previously reported to be methylated in neoplasia. FBN2 has recently been reported to be epigenetically silenced in colorectal, oesophageal and non-small-cell lung cancers (Chen et al, 2005;Tsunoda et al, 2009;Yagi et al, 2010). QPCT, which encodes a glutaminyl cyclase (Fischer and Spiess, 1987;Pohl et al, 1991), is frequently methylated in malignant melanoma (Muthusamy et al, 2006).…”

TMEFF2 Deregulation Contributes to Gastric Carcinogenesis and Indicates Poor Survival Outcome

“…The deregulation of TMEFF2 has been demonstrated in various tumor types (10,12,27). However, the biologic functions and clinical implication of TMEFF2 in gastric cancer remain unknown.…”