RRC ID 17616
Author Seto M, Ohta M, Ikenoue T, Sugimoto T, Asaoka Y, Tada M, Mohri D, Kudo Y, Ijichi H, Tateishi K, Otsuka M, Hirata Y, Maeda S, Koike K, Omata M.
Title Reduced expression of RAS protein activator like-1 in gastric cancer.
Journal Int. J. Cancer
Abstract 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.
Volume 128(6)
Pages 1293-302
Published 2011-3-15
DOI 10.1002/ijc.25459
PMID 20473946
MeSH Adult Aged Aged, 80 and over Blotting, Western Cell Proliferation DNA Methylation* Disease Progression Epigenesis, Genetic* Female Gene Silencing Humans Immunoenzyme Techniques Loss of Heterozygosity* Lymphatic Metastasis Male Middle Aged Mutation / genetics* Neoplasm Invasiveness Promoter Regions, Genetic / genetics RNA, Messenger / genetics Reverse Transcriptase Polymerase Chain Reaction Stomach Neoplasms / genetics* Stomach Neoplasms / metabolism Stomach Neoplasms / pathology Tumor Cells, Cultured ras GTPase-Activating Proteins / genetics* ras GTPase-Activating Proteins / metabolism*
IF 7.36
Times Cited 14
Human and Animal Cells MKN7 (RCB0999) MKN45 (RCB1001) MKN74 (RCB1002) MKN1 (RCB1003)