TY - JOUR
T1 - Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia
AU - Tsuchiya, Takashi
AU - Tamura, Gen
AU - Sato, Kiyoshi
AU - Endoh, Yasushi
AU - Sakata, Ken
AU - Jin, Zhe
AU - Motoyama, Teiichi
AU - Usuba, Osamu
AU - Kimura, Wataru
AU - Nishizuka, Satoshi
AU - Wilson, Keith T.
AU - James, Stephen P.
AU - Yin, Jing
AU - Fleisher, A. Steven
AU - Zou, Tongtong
AU - Silverberg, Steven G.
AU - Kong, Dehe
AU - Meltzer, Stephen J.
N1 - Funding Information:
This work was supported in part by a Grant-in-Aid for Cancer Research (No. 10-3) from the Ministry of Health and Welfare of Japan. This work was also supported in part by NIH grants CA85069, CA78843, CA77057, DK47717 and DK53620, and by the Medical Research Service, Department of Veterans Affairs.
PY - 2000/7/27
Y1 - 2000/7/27
N2 - The adenomatous polyposis coli (APC) tumor suppressor gene is mutationally inactivated in both familial and sporadic forms of colorectal ranters. In addition, hypermethylation of CpG islands in the upstream portion of APC, a potential alternative mechanism of tumor suppressor gene inactivation, has been described in colorectal cancer. Because a subset of both gastric and colorectal cancers display the CpG island methylator phenotype, we hypothesized that epigenetic inactivation of APC was likely to occur in at least same gastric cancers. A PC exhibits two forms of transcripts from exons 1A and 1B in the stomach. Therefore, we investigated CpG island methylation in the sequences upstream of exons 1A and 1B, i.e., promoters 1A and 1B respectively. We calculated DNAs from 10 gastric cancer cell lines, 40 primary gastric cancers, and 40 matching non-cancerous gastric mucosae. Methylated alleles of promoter 1A were present in 10 (100%) of 10 gastric cancer cell lines, 33 (82.5%,) of 40 primary gastric cancers, and 39 (97.5%) of 40 noncancerous gastric mucosae. In contrast, promoter 1B was unmethylated in all of these same samples. APC transcripts from exon 1A were not expressed in nine of the 10 methylated gastric cancer cell lines, whereas APC transcripts were expressed from exon 1B. Thus, expression from a given promoter correlated well with its methylation status. We conclude that in contrast to the colon, methylation of promoter 1A is a normal event in the stomach; moreover, promoter 1B is protected from methylation in the stomach and thus probably does not participate in this form of epigenetic APC inactivation.
AB - The adenomatous polyposis coli (APC) tumor suppressor gene is mutationally inactivated in both familial and sporadic forms of colorectal ranters. In addition, hypermethylation of CpG islands in the upstream portion of APC, a potential alternative mechanism of tumor suppressor gene inactivation, has been described in colorectal cancer. Because a subset of both gastric and colorectal cancers display the CpG island methylator phenotype, we hypothesized that epigenetic inactivation of APC was likely to occur in at least same gastric cancers. A PC exhibits two forms of transcripts from exons 1A and 1B in the stomach. Therefore, we investigated CpG island methylation in the sequences upstream of exons 1A and 1B, i.e., promoters 1A and 1B respectively. We calculated DNAs from 10 gastric cancer cell lines, 40 primary gastric cancers, and 40 matching non-cancerous gastric mucosae. Methylated alleles of promoter 1A were present in 10 (100%) of 10 gastric cancer cell lines, 33 (82.5%,) of 40 primary gastric cancers, and 39 (97.5%) of 40 noncancerous gastric mucosae. In contrast, promoter 1B was unmethylated in all of these same samples. APC transcripts from exon 1A were not expressed in nine of the 10 methylated gastric cancer cell lines, whereas APC transcripts were expressed from exon 1B. Thus, expression from a given promoter correlated well with its methylation status. We conclude that in contrast to the colon, methylation of promoter 1A is a normal event in the stomach; moreover, promoter 1B is protected from methylation in the stomach and thus probably does not participate in this form of epigenetic APC inactivation.
KW - APC
KW - Gastric cancer
KW - Hypermethylation
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U2 - 10.1038/sj.onc.1203704
DO - 10.1038/sj.onc.1203704
M3 - Article
C2 - 10951570
AN - SCOPUS:0034721079
SN - 0950-9232
VL - 19
SP - 3642
EP - 3646
JO - Oncogene
JF - Oncogene
IS - 32
ER -