Reduced expression of RAS protein activator like-1 in gastric cancer.
RAS signaling is frequently deregulated in human neoplasms. However, RAS mutations have been found in only a small proportion of human gastric cancers, implicating other mechanisms in the activation of RAS signaling in gastric tumorigenesis. We have previously reported that decreased expression of RAS protein activator like-1 (RASAL1), a member of the RAS-GTPase-activating proteins that switch off RAS activity, contributes to colon tumor progression. In our study, we explored the involvement of decreased RASAL1 expression in gastric tumorigenesis. RASAL1 expression was reduced in 6 of 10 gastric cancer cell lines examined by immunoblotting. Knockdown of RASAL1 increased mitogen-activated protein kinase signaling in response to growth factor stimulation, and the forced expression of RASAL1 reduced proliferation of gastric cancer cells. Immunohistochemical analyses in primary gastric tumors showed that RASAL1 expression was reduced in 23 of 48 (48%) of the gastric cancers but in none of the adenomas (0/10). Methylation of the RASAL1 promoter region and loss of heterozygosity (LOH) at the RASAL1 locus were examined to investigate the causes of RASAL1 silencing. All cell lines with reduced RASAL1 had RASAL1 methylation, and two had LOH. In primary gastric cancers, methylation or LOH was detected in 50% (6/12) of those with reduced RASAL1. Furthermore, RASAL1 expression was restored in some cell lines by histone deacetylase inhibitor treatment. Our findings demonstrate that reduced RASAL1 expression, partly due to genetic and epigenetic changes, contributes to gastric carcinogenesis, and also re-emphasize the importance of RAS signaling in gastric cancer development.
Seto
Motoko
M
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. seto@kanto-ctr-hsp.com
Ohta
Miki
M
Ikenoue
Tsuneo
T
Sugimoto
Takafumi
T
Asaoka
Yoshinari
Y
Tada
Motohisa
M
Mohri
Dai
D
Kudo
Yotaro
Y
Ijichi
Hideaki
H
Tateishi
Keisuke
K
Otsuka
Motoyuki
M
Hirata
Yoshihiro
Y
Maeda
Shin
S
Koike
Kazuhiko
K
Omata
Masao
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D049109:Cell Proliferation; D019175:DNA Methylation; D018450:Disease Progression; D044127:Epigenesis, Genetic; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007124:Immunoenzyme Techniques; D019656:Loss of Heterozygosity; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D020703:ras GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism*
D012333:RNA, Messenger; D020703:ras GTPase-Activating Proteins