Genomic imprinting and carcinogenesis
| Project/Area Number | 15591758 |
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Obstetrics and gynecology
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
ARIMA Takahiro Kyushu University, Medical Institute of Bioregulation, Research Associate, 生体防御医学研究所, 助手 (80253532)
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| Co-Investigator(Kenkyū-buntansha) |
KATO Kiyoko Kyushu University, Medical Institute of Bioregulation, Assistant Professor, 生体防御医学研究所, 講師 (10253527)
KATO Hidenori Kyushu University, Medical Institute of Bioregulation, Assistant Professor, 大学病院, 講師 (60214392)
MATSUDA Takao Kyushu University, Medical Institute of Bioregulation, Research Associate, 大学病院, 助手 (10304825)
WAKE Norio Kyushu University, Medical Institute of Bioregulation, Professor, 生体防御医学研究所, 教授 (50158606)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed(Fiscal Year 2004)
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| Budget Amount *help |
¥3,500,000 (Direct Cost : ¥3,500,000)
Fiscal Year 2004 : ¥1,300,000 (Direct Cost : ¥1,300,000)
Fiscal Year 2003 : ¥2,200,000 (Direct Cost : ¥2,200,000)
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| Keywords | Genomic imprinting / Tumor suppressor gene / ZAC / Apoptosis / Ovarian cancer / DNA methylation / カスパーゼ / Kip2 / LIT1 / メチル化 |
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| Research Abstract |
ZAC is a paternally expressed, imprinted gene located on chromosome 6q24,within a region known to harbor a tumor suppressor gene for several types of neoplasia, including human ovarian cancer(HOC). We, and others, have failed to identify genetic mutations in the ZAC gene in tumor material. However, many imprinted genes contain differentially allele-specific-methylated regions(DMRs) and harbor promoter activity that is regulated by the DNA methylation. Aberrant DNA methylation is a common feature of neoplasia and changes in DNA methylation at the ZAC locus have been reported in some cases of HOC. We investigated the DNA methylation and ZAC mRNA expression levels in a larger sample of primary HOC material, obtained by Laser Capture Microdissection. ZAC mRNA expression was reduced in the majority of samples and this correlated with hypermethylation of the ZAC-DMR. Treatment of hypermethylated cells lines with a demethylating agent restored ZAC expression. Our studies indicate that transcriptional silencing of ZAC is likely to be caused by DNA methylation in HOC. Forced expression of ZAC resulted in a reduction in proliferation and marked induction of apoptotic cell death. The ZAC-mediated apoptosis signal is p53-independent and eliminated by inhibitors of caspase 3,8 and 9. Reduced expression of ZAC would therefore favor tumor progression. As there were no significant differences in either DNA methylation or expression of ZAC mRNA between localized and advanced tumors, our data indicates that loss of ZAC is a relatively early event in HOC.
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Report
(3results)
Research Products
(16results)
