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Genomic imprinting and carcinogenesis

Research Project

Project/Area Number 15591758
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Obstetrics and gynecology
Research InstitutionKYUSHU UNIVERSITY

Principal Investigator

ARIMA Takahiro  Kyushu University, Medical Institute of Bioregulation, Research Associate, 生体防御医学研究所, 助手 (80253532)

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)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
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)
KeywordsGenomic imprinting / Tumor suppressor gene / ZAC / Apoptosis / Ovarian cancer / DNA methylation / カスパーゼ / Kip2 / LIT1 / メチル化
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.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (16 results)

All 2005 2004 Other

All Journal Article (11 results) Publications (5 results)

  • [Journal Article] ZAC, LIT1 (KCNQ10T1) and p57KIP2 (CDKN1C) are in an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome.2005

    • Author(s)
      Takahiro Arima et al.
    • Journal Title

      Nucleic Acids Research 33(8)

      Pages: 2650-2660

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer.2005

    • Author(s)
      Kamikihara et al.
    • Journal Title

      Int.J.Cancer 115

      Pages: 690-700

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] インプリントと生殖異常2005

    • Author(s)
      有馬隆博, 他
    • Journal Title

      Molecular Medicine 42,2

      Pages: 195-200

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ZAC,LIT1(KCNQ1OT1) and p57KIP2(CDKN1C) are in an imprinted gene network that may play a role in Beckwith-Wiedemann syndrome.2005

    • Author(s)
      Takahiro Arima et al.
    • Journal Title

      Nucleic Acids Research 33(8)

      Pages: 2650-2660

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] インプリントと生殖異常2005

    • Author(s)
      有馬隆博他
    • Journal Title

      Molecular Medicine 42・2

      Pages: 195-200

    • Related Report
      2004 Annual Research Report
  • [Journal Article] K-Ras and H-Ras activation promote distinct consequences on endomerial cell survival.2004

    • Author(s)
      Ninomiya Y et al.
    • Journal Title

      Cancer Reserch 64

      Pages: 2759-2765

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ゲノムインプリントと生殖補助技術2004

    • Author(s)
      上木原哲也, 他
    • Journal Title

      産婦人科の世界 56

      Pages: 271-276

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] K-Ras and H-Ras activation promote distinct consequences on endometrial cell survival.2004

    • Author(s)
      Ninomiya Y et al.
    • Journal Title

      Cancer Reserch 64

      Pages: 2759-2765

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] K-Ras and H-Ras activation promote distinct consequences on endometrial cell survival.2004

    • Author(s)
      Ninomiya Y et al.
    • Journal Title

      Cancer Research 64

      Pages: 2759-2765

    • Related Report
      2004 Annual Research Report
  • [Journal Article] ゲノムインプリントと生殖補助技術2004

    • Author(s)
      上木原哲也他
    • Journal Title

      産婦人科の世界 56

      Pages: 271-276

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Epigenetic silencing of the imprinted gene ZAC by DNA methylation is an early event in the progression of human ovarian cancer.

    • Author(s)
      Kamikihara et al.
    • Journal Title

      International Journal of Cancer (in press)

    • Related Report
      2004 Annual Research Report
  • [Publications] Asanoma K, et al.: "NECC1, a candidate choriocarcinoma suppressor gene which encodes homeodomain cosensus motif"Genomics. 81. 15-25 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ueoka Y, et al.: "Hepatocyte growth factor modulates motility and invasiveness of ovarian carcinomas via Ras mediated pathway"Molecular and cellular endocrinology. 202. 80-88 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamayoshi A, et al.: "Photodynamic antisense therapy : regulation of cervical carcinoma cells by psoralen-conjugated oligonucleotides"Nucleic Acid Research Supplement. 3. 75-76 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Matsuda T, et al.: "Genetics and molecular markers in gestational trophoblastic desease with special reference to their clinical application"Best Practice & Research Clinical Obstetrics and Gynecology. 17,6. 827-836 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Oudejans CBM, et al.: "The parent - of - origin effect of 10q22 coincides with two regions enriched for genes with downregulated expression in androgenetic placenta"Human Molecular Genetics. (in press). (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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