title: Epigenetic inactivation of RASSF2 in oral squamous cell carcinoma.
abstract: Genetic and epigenetic alterations in tumor-suppressor genes play important roles in human neoplasia. Ras signaling is often activated in oral squamous cell carcinoma (OSCC), although Ras mutations are rarely detected in Japanese OSCC patients, and the mechanisms underlying the gene's activation remain unclear. Here, we examined the expression of Ras association family (RASSF) genes in a panel of OSCC cell lines and found that RASSF2 is often downregulated by DNA methylation in OSCC cells. In addition, aberrant methylation of RASSF2 was detected in 12 of 46 (26%) primary OSCC, and 18 (39%) of those OSCC showed methylation of at least one RASSF gene. Ectopic expression of RASSF2 in OSCC cells suppressed cell growth and induced apoptosis. A RASSF2 deletion mutant lacking the Ras-association domain, which was therefore unable to interact with Ras, exhibited less pro-apoptotic activity than the full-length protein, indicating that the pro-apoptotic activity of RASSF2 is related to its association with Ras. Genomic screening of genes regulated by RASSF2 showed that genes involved in immune responses, angiogenesis, and metastasis are suppressed by RASSF2. Our results suggest that epigenetic inactivation of RASSF2 plays an important role in OSCC tumorigenesis, and that RASSF2 may be a useful molecular target for the diagnosis and treatment of OSCC.
authors.affiliation: Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Sapporo 060-8543, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Imai
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.forename: Hiromu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Kimishige
authors.initials: K
authors.lastname: Akino
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogi
authors.forename: Yohei
authors.initials: Y
authors.lastname: Sogabe
authors.forename: Lisa
authors.initials: L
authors.lastname: Kashima
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.forename: Masanori
authors.initials: M
authors.lastname: Nojima
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mita
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sasaki
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: Hiroyoshi
authors.initials: H
authors.lastname: Hiratsuka
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
mesh_terms: D017209:Apoptosis; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D006801:Humans; D007150:Immunohistochemistry; D009062:Mouth Neoplasms / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics*; D025521:Tumor Suppressor Proteins
chemical_list: D011506:Proteins; C425300:RASSF2 protein, human; D025521:Tumor Suppressor Proteins