Skip Navigation



Carcinogenesis Advance Access published online on February 29, 2008
Carcinogenesis, doi:10.1093/carcin/bgn060
This Article
Right arrow Advance Access manuscript (PDF) Freely available
Right arrow Supplementary Data
Right arrowOA All Versions of this Article:
29/7/1312    most recent
bgn060v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Maruyama, R.
Right arrow Articles by Tokino, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Maruyama, R.
Right arrow Articles by Tokino, T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

Cytoplasmic RASSF2A is a Pro-apoptotic Mediator Whose Expression is Epigenetically Silenced in Gastric Cancer

Reo Maruyama1,2,8, Kimishige Akino1,2,8, Minoru Toyota1,2,*, Hiromu Suzuki1, Takashi Imai2,3, Mutsumi Ohe-Toyota2, Eiichiro Yamamoto1, Masanori Nojima4, Tomoko Fujikane2,5, Yasushi Sasaki2, Toshiharu Yamashita6, Yoshiyuki Watanabe2,7, Hiroyoshi Hiratsuka3, Koichi Hirata5, Fumio Itoh7, Kohzoh Imai1, Yasuhisa Shinomura1,* and Takashi Tokino2

1 First Department of Internal Medicine
2 Department of Molecular Biology, Cancer Research Institute
3 Department of Oral Surgery
4 Department of Public Health
5 First Department of Surgery
6 Department of Dermatology, Sapporo Medical University, Sapporo 060-8556, Japan
7 Department of Gastroenterology and Hepatology, Saint Marianna University, School of Medicine, Kawasaki 216-8511, Japan

* Correspondence should be addressed to: Minoru Toyota or Yasuhisa Shinomura, First Department of Internal Medicine, Sapporo Medical University, South 1,West 17, Chuo-ku, Sapporo 060-8543, Japan, Tel: 11-611-2111 (Ext. 2387), Fax: 11-618-3313, E-mail: mtoyota{at}sapmed.ac.jp or shinomura{at}sapmed.ac.jp

Gastric cancer cells often show altered Ras signaling, though the underlying molecular mechanism is not fully understood. We examined the expression profile of eight RASSF genes plus MST1/2 and found that RASSF2A is the most frequently downregulated in gastric cancer. RASSF2A was completely silenced in six of ten gastric cancer cell lines as a result of promoter methylation, and expression was restored by treating the cells with 5-aza-2’-deoxycytidine. Introduction of RASSF2A into non-expressing cell lines suppressed colony formation and induced apoptosis. These effects were associated with the cytoplasmic localization of RASSF2A and morphological changes to the cells. cDNA microarray analysis revealed that RASSF2A suppresses expression of inflammatory cytokines, which may in turn suppress angiogenesis and invasion. In primary gastric cancers, aberrant methylation of RASSF2A was detected in 23 of 78 (29.5%) cases, and methylation correlated significantly with an absence of the lymphatic invasion, absence of venous invasion, absence of lymph node metastasis, less advanced stages, Epstein-Barr virus, absence of p53 mutations and the presence of the CpG island methylator phenotype-high. These results suggest that epigenetic inactivation of RASSF2A is required for tumorigenesis in a subset of gastric cancers.

Key Words: DNA methylation • gene expression • apoptosis

8 These authors contribute equally to the work.

Received October 12, 2007; revised January 22, 2008; accepted February 24, 2008.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?




Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.