title: BCL2L10 is frequently silenced by promoter hypermethylation in gastric cancer.
abstract: In gastric cancer, several tumor suppressor and tumor-related genes are silenced by aberrant methylation. Previously, we demonstrated that BCL2L10, which belongs to the pro-apoptotic Bcl-2 family, was transcriptionally repressed by promoter hypermethylation and that its overexpression caused apoptosis and growth inhibition of gastric cancer cells. In this study, we investigated the methylation status of BCL2L10 and its expression in 21 gastric cancer tissues and corresponding non-neoplastic mucosae along with the methylation status of p16, RUNX3, and hMLH1 genes by using methylation specific PCR. In addition, we examined the association between the methylation status of each gene and the expression of EZH2, which was associated with DNA methylation of its target genes. As a result, aberrant methylation of BCL2L10 was detected in 38% of gastric cancer and in 24% of corresponding non-neoplastic mucosae and correlated with low expression of BCL2L10. Methylation of p16, RUNX3, and hMLH1 was found in gastric cancer and in corresponding non-neoplastic mucosae at almost similar frequencies as previous reports. Expression of EZH2 was detected more frequently in tumors (48%) as compared to corresponding non-neoplastic mucosae (10%) (p=0.006), however, no significant difference was found between expression of EZH2 and the methylation frequency of each gene. In conclusion, our data suggest that silencing of BCL2L10 by aberrant methylation is a common feature in gastric cancer and its inactivation may be involved in the early steps of gastric carcinogenesis.
authors.affiliation: Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Mikata
authors.forename: Kenichi
authors.initials: K
authors.lastname: Fukai
authors.forename: Fumio
authors.initials: F
authors.lastname: Imazeki
authors.forename: Makoto
authors.initials: M
authors.lastname: Arai
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yonemitsu
authors.forename: Kaiyu
authors.initials: K
authors.lastname: Zhang
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Nabeya
authors.forename: Takenori
authors.initials: T
authors.lastname: Ochiai
authors.forename: Osamu
authors.initials: O
authors.lastname: Yokosuka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D063151:Polycomb Repressive Complex 2; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C117144:BCL2-like 10 protein; C000614131:CDKN2A protein, human; D050677:Core Binding Factor Alpha 3 Subunit; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C493729:Runx3 protein, human; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D000070957:MutL Protein Homolog 1