1. ¹Department of Molecular Oncology, Graduate School of Medicine and Dentistry, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan
2. ²The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

Correspondence: Professor Y Yuasa, 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. E-mail: yuasa.monc@tmd.ac.jp

³These authors contributed equally to this work.

Received 3 June 2005; Revised 31 October 2005; Accepted 6 November 2005; Published online 12 December 2005.

Abstract

Recently, it was reported that exogenous bone morphogenetic protein (BMP)-2 acted as an antiproliferative agent in a variety of cell lines, including normal and cancerous gastric cell lines, indicating that BMP-2 plays an important role during cell growth. However, despite the loss of BMP-2 expression in several cancers, the underlying mechanism remains unknown. Epigenetic silencing through DNA methylation is one of the key steps during carcinogenesis. In this study, we found, through analysis by the methylation-specific polymerase chain reaction technique, CpG island methylation of the BMP-2 promoter region in gastric and colon cancer cell lines. BMP-2 mRNA was found to be activated after 5-aza-2'-deoxycytidine treatment of the methylation-positive cells. Moreover, 24 of the 56 (42.9%) gastric cancer tissues exhibited promoter methylation. Immunohistochemical staining revealed that 18 of the 24 (75%) gastric cancer tissues without methylation signals exhibited BMP-2 expression, whereas among 20 cancer tissues with strong methylation signals only four (20%) expressed BMP-2 (P=0.0003). These findings indicate that BMP-2 methylation is strongly associated with the loss of BMP-2 protein expression in the primary gastric carcinomas. BMP-2 methylation was more often observed in diffuse type (60.7%) than in intestinal type (25%) gastric carcinomas (P=0.007). Thus, aberrant BMP-2 methylation and the resultant loss of BMP-2 expression may be related to gastric carcinogenesis, particularly in the diffuse type.