Alterations and hypermethylation of the p14(ARF) gene in gastric cancer.
p14(ARF), generated through an alternative splicing process that replaces the first exon, 1alpha, of p16(INK4a) with exon 1beta, located >15 kb upstream of exon 1alpha, has been shown to function as a growth suppressor. We examined 11 gastric cancer cell lines for mRNA expression, homozygous deletion, mutation, and promoter methylation of the p14(ARF) gene. No mRNA expression was detected in 5 of the 7 diffuse-type cell lines. All intestinal cell lines displayed normal levels of expression except for one with a low level of expression. Of the 5 cell lines without expression, 3 (MKN45, NUGC-2, and NUGC-4) and 1 (KATO III) displayed homozygous deletion and methylation of the p14(ARF) gene, respectively. No mutation was found in the whole coding region of the p14(ARF) gene in 8 cell lines without homozygous deletion. Our results indicate that the p14(ARF) gene is more frequently inactivated by homozygous deletion or methylation in diffuse-type gastric cancer cell lines (5/7, 71.4%) than in intestinal ones (0/4, P = 0.022). When we also analyzed 62 primary gastric cancers for the methylation status of the p14(ARF) promoter region, the methylation frequency tended to be higher in diffuse-type gastric cancers (15/33, 45.5%) than in intestinal ones (7/28, 25%). Thus, p14(ARF) alterations might be involved in diffuse-type gastric carcinogenesis.
Second Department of Surgery, Tokyo Medical and Dental University School of Medicine, Tokyo, Japan.
S
S
Iida
Y
Y
Akiyama
T
T
Nakajima
W
W
Ichikawa
Z
Z
Nihei
K
K
Sugihara
Y
Y
Yuasa
D002352:Carrier Proteins / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019175:DNA Methylation; D017353:Gene Deletion; D015870:Gene Expression; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000502:physiology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000235:genetics*; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011506:Proteins; D012333:RNA, Messenger; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53