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Carcinogenesis Advance Access originally published online on February 29, 2008
Carcinogenesis 2008 29(7):1312-1318; doi:10.1093/carcin/bgn060
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Cytoplasmic RASSF2A is a proapoptotic mediator whose expression is epigenetically silenced in gastric cancer

Reo Maruyama1,2,{dagger}, Kimishige Akino1,2,{dagger}, 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

* To whom correspondence should be addressed. Tel: +81 11 611 2111 ext. 3210; Fax: +81 11 611 2282; Email: mtoyota{at}sapmed.ac.jp

Correspondence may also be addressed to Yasuhisa Shinomura. Email: 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 ras-association domain family (RASSF) genes plus MST1/2 and found that RASSF2A is the most frequently downregulated in gastric cancer. RASSF2A was completely silenced in 6 of 10 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. Complementary DNA microarray analysis revealed that RASSF2A suppresses the 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.

Abbreviations: 5-aza-dC, 5-aza-2'-deoxycytidine; CIMP, CpG island methylator phenotype; NLS, nuclear localization signal; PCR, polymerase chain reaction; RA, Ras association

{dagger} These authors contributed equally to this work.

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


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