title: Cytoplasmic RASSF2A is a proapoptotic mediator whose expression is epigenetically silenced in gastric cancer.
abstract: 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.
authors.affiliation: First Department of Internal Medicine, Sapporo Medical University, Sapporo 060-8556, Japan.
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.forename: Kimishige
authors.initials: K
authors.lastname: Akino
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Imai
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Ohe-Toyota
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Yamamoto
authors.forename: Masanori
authors.initials: M
authors.lastname: Nojima
authors.forename: Tomoko
authors.initials: T
authors.lastname: Fujikane
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yamashita
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Hiratsuka
authors.forename: Koichi
authors.initials: K
authors.lastname: Hirata
authors.forename: Fumio
authors.initials: F
authors.lastname: Itoh
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000235:genetics*; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D008969:Molecular Sequence Data; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025521:Tumor Suppressor Proteins
chemical_list: D011506:Proteins; C425300:RASSF2 protein, human; D025521:Tumor Suppressor Proteins