Epigenetic inactivation of the RAS-effector gene RASSF2 in lung cancers.
RASSF2, a member of the RAS association domain family 1 (RASSF1), is a candidate tumor suppressor gene (TSG) that is silenced by promoter hypermethylation in several human cancers. In this study, we examined the expression of RASSF2 mRNA and the promoter methylation status in lung cancer cell lines and in tumor samples of 106 primary non-small cell lung cancers (NSCLCs) by methylation-specific PCR. RASSF2 expression was absent in 26% of small cell lung cancers (SCLCs; n=27 lines) and 50% of NSCLCs (n=42 lines). Promoter methylation of RASSF2 was found in 18% of the SCLC cell lines (n=22) and 62% of the NSCLC cell lines (n=26), and the methylation status was tightly associated with the loss of RASSF2 expression. RASSF2 expression was restored by treatment with 5-aza-2-deoxycytidine and/or trichostatin-A in the NSCLC cell lines which were absent of the expression. RASSF2 methylation was found in 31% of primary NSCLC tumors, and methylation was more frequent in the specimens from non-smokers (18 of 40, 45%) than in the specimens from smokers (15 of 66, 23%, P=0.014). We also examined the association of RASSF2 methylation with mutations of KRAS and EGFR and with promoter hypermethylation of RASSF1A; however, we could not find a significant association between RASSF2 methylation and these genetic and epigenetic changes. Our results indicate that aberrant methylation of the RASSF2 gene with the subsequent loss of RASSF2 expression plays an important role in the pathogenesis of lung cancers.
Kaira
Kyoichi
K
Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan.
Sunaga
Noriaki
N
Tomizawa
Yoshio
Y
Yanagitani
Noriko
N
Ishizuka
Tamotsu
T
Saito
Ryusei
R
Nakajima
Takashi
T
Mori
Masatomo
M
D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
C117307:KRAS protein, human; D011506:Proteins; D011518:Proto-Oncogene Proteins; C411762:RASSF1 protein, human; C425300:RASSF2 protein, human; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins