Original Article
Copyright ©2010 Baishideng. All rights reserved.
World J Gastroenterol. Mar 14, 2010; 16(10): 1201-1208
Published online Mar 14, 2010. doi: 10.3748/wjg.v16.i10.1201
Methylation of GATA-4 and GATA-5 and development of sporadic gastric carcinomas
Xian-Zi Wen, Yoshimitsu Akiyama, Kai-Feng Pan, Zhao-Jun Liu, Zhe-Ming Lu, Jing Zhou, Lian-Kun Gu, Cai-Xuan Dong, Bu-Dong Zhu, Jia-Fu Ji, Wei-Cheng You, Da-Jun Deng
Xian-Zi Wen, Zhao-Jun Liu, Zhe-Ming Lu, Jing Zhou, Lian-Kun Gu, Da-Jun Deng, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Etiology, Peking University School of Oncology and Beijing Cancer Hospital & Institute, Fucheng Road No. 52, Haidian District, Beijing 100142, China
Yoshimitsu Akiyama, Department of Molecular Oncology, Graduate School of Medicine and Dentistry, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
Kai-Feng Pan, Cai-Xuan Dong, Wei-Cheng You, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Epidemiology, Peking University School of Oncology and Beijing Cancer Hospital, Fucheng Road No. 52, Haidian District, Beijing 100142, China
Bu-Dong Zhu, Department of Internal Medicine, Peking University School of Oncology and Beijing Cancer Hospital, Fucheng Road No. 52, Haidian District, Beijing 100142, China
Jia-Fu Ji, Department of Surgery, Peking University School of Oncology and Beijing Cancer Hospital, Fucheng Road No. 52, Haidian District, Beijing 100142, China
Author contributions: Wen XZ participated in the study design and conducted methylation specific polymerase chain reaction, clone sequencing, immunohistochemical staining assays and wrote the manuscript; Akiyama Y participated in the study design; Pan KF, Dong CX and You WC conducted the 13C-breath test and collected gastric dysplasia samples from subjects in Linqu County; Liu ZJ quantified GATA-4 methylation by denatured high performance liquid chromatography; Lu ZM analyzed Helicobacter pylori by polymerase chain reaction; Zhou J extracted genetic DNA from all tissue samples; Gu LK prepared gastric cancer tissue sections; Zhu BD collected the gastric biopsies from the outpatients; Ji JF collected the paired sporadic gastric carcinomas at Beijing Cancer Hospital; Deng DJ designed and coordinated the study, analyzed the data, and revised the manuscript.
Supported by (in part) National High Technology R&D Program, No. 2006AA02A402 and No. 2010CB529300-G, and NSFC Grant, No. 30921140311 to Deng DJ
Correspondence to: Da-Jun Deng, Professor, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Etiology, Peking University School of Oncology and Beijing Cancer Hospital & Institute, Fucheng Road No. 52, Haidian District, Beijing 100142, China. dengdajun@bjmu.edu.cn
Telephone: +86-10-88196752   Fax: +86-10-88122437
Received: November 25, 2009
Revised: December 10, 2009
Accepted: December 17, 2009
Published online: March 14, 2010
Abstract

AIM: To understand the implication of GATA-4 and GATA-5 methylation in gastric carcinogenesis.

METHODS: Methylation status of GATA-4 and GATA-5 CpG islands in human gastric mucosa samples, including normal gastric biopsies from 45 outpatients, gastric dysplasia [low-grade gastric intraepithelial neoplasia (GIN), n = 30; indefinite, n = 77], and 80 paired sporadic gastric carcinomas (SGC) as well as the adjacent non-neoplastic gastric tissues was analyzed by methylation specific polymerase chain reaction (MSP) and confirmed by denatured high performance liquid chromatography (DHPLC). Immunohistochemical staining was used to detect protein expression. The correlation between GATA-4 and GATA-5 methylation and clinicopathological characteristics of patients including Helicobacter pylori (H. pylori) infection was analyzed.

RESULTS: GATA-4 and GATA-5 methylation was frequently observed in SGCs (53.8% and 61.3%, respectively) and their corresponding normal tissues (41.3% and 46.3%) by MSP. The result of MSP was consistent with that of DHPLC. Loss of both GATA-4 and GATA-5 proteins was associated with their methylation in SGCs (P = 0.01). Moreover, a high frequency of GATA-4 and GATA-5 methylation was found in both gastric low-grade GIN (57.1% and 69.0%) and indefinite for dysplasia (42.9% and 46.7%), respectively. However, GATA-4 and GATA-5 methylation was detected only in 4/32 (12.5%) and 3/39 (7.7%) of normal gastric biopsies. GATA-4 methylation in both normal gastric mucosa and low-grade GIN was also significantly associated with H. pylori infection (P = 0.023 and 0.027, two-sides).

CONCLUSION: Epigenetic inactivation of GATA-4 (and GATA-5) by methylation of CpG islands is an early frequent event during gastric carcinogenesis and is significantly correlated with H. pylori infection.

Keywords: Dysplasia; Gastric carcinoma; GATA-4; GATA-5; Helicobacter pylori; Methylation