Journal Article

Cytoplasmic RASSF2A is a proapoptotic mediator whose expression is epigenetically silenced in gastric cancer

Reo Maruyama, Kimishige Akino, Minoru Toyota, Hiromu Suzuki, Takashi Imai, Mutsumi Ohe-Toyota, Eiichiro Yamamoto, Masanori Nojima, Tomoko Fujikane, Yasushi Sasaki, Toshiharu Yamashita, Yoshiyuki Watanabe, Hiroyoshi Hiratsuka, Koichi Hirata, Fumio Itoh, Kohzoh Imai, Yasuhisa Shinomura and Takashi Tokino

in Carcinogenesis

Volume 29, issue 7, pages 1312-1318
Published in print July 2008 | ISSN: 0143-3334
Published online February 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgn060

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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.

Journal Article.  4932 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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