Epigenetic inactivation of RASSF2 in oral squamous cell carcinoma.
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.
Imai
Takashi
T
Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Sapporo 060-8543, Japan.
Toyota
Minoru
M
Suzuki
Hiromu
H
Akino
Kimishige
K
Ogi
Kazuhiro
K
Sogabe
Yohei
Y
Kashima
Lisa
L
Maruyama
Reo
R
Nojima
Masanori
M
Mita
Hiroaki
H
Sasaki
Yasushi
Y
Itoh
Fumio
F
Imai
Kohzoh
K
Shinomura
Yasuhisa
Y
Hiratsuka
Hiroyoshi
H
Tokino
Takashi
T
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
D011506:Proteins; C425300:RASSF2 protein, human; D025521:Tumor Suppressor Proteins