Methylation of CLDN6, FBN2, RBP1, RBP4, TFPI2, and TMEFF2 in esophageal squamous cell carcinoma.
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.
Tsunoda
Shigeru
S
Discipline of Surgery, The University of Adelaide, South Australia 5005, Australia. tsunoda@kuhp.kyoto-u.ac.jp
Smith
Eric
E
De Young
Neville J
NJ
Wang
Xian
X
Tian
Zi-Qing
ZQ
Liu
Jun-Feng
JF
Jamieson
Glyn G
GG
Drew
Paul A
PA
D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D045744:Cell Line, Tumor; D057167:Claudins; D019175:DNA Methylation; D004938:Esophageal Neoplasms / Q000235:genetics*; D000071840:Fibrillin-2; D000071837:Fibrillins; D020868:Gene Silencing; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D054840:Retinol-Binding Proteins, Cellular / Q000235:genetics*; D054839:Retinol-Binding Proteins, Plasma / Q000235:genetics*
D057167:Claudins; C000605723:FBN2 protein, human; D000071840:Fibrillin-2; D000071837:Fibrillins; D006023:Glycoproteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009363:Neoplasm Proteins; C518456:RBP1 protein, human; C101326:RBP4 protein, human; D054840:Retinol-Binding Proteins, Cellular; D054839:Retinol-Binding Proteins, Plasma; C423567:TMEFF2 protein, human; C021240:tissue-factor-pathway inhibitor 2; C122101:claudin 6