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Molecular targeted therapy by inducing cancer cell senesence

Research Project

Project/Area Number 14104014
Research Category

Grant-in-Aid for Scientific Research (S)

Allocation TypeSingle-year Grants
Research Field Obstetrics and gynecology
Research InstitutionKYUSHU UNIVERCITY

Principal Investigator

WAKE Norio  Kyushu University, Faculty of Medicine, Professor, 医学研究院, 教授 (50158606)

Co-Investigator(Kenkyū-buntansha) KOBAYASHI Hiroaki  Kyushu University, Hospital, Assistant Professor, 病院・講師 (70260700)
KATO Kiyoko  Kyushu University, Medical Institute of Bioregulation, Assistant Professor, 生体防御医学研究所, 講師 (10253527)
SONODA Kenzo  Kyushu University, Hospital, Research Associate, 病院・助手 (30294929)
UEOKA Yosuke  Kyushu University, Hospital, Research Associate, 病院・助手 (50372743)
平川 俊夫  九州大学, 大学病院, 講師 (20218770)
浅野間 和夫  九州大学, 生体防御医学研究所, 助手 (30380413)
井上 貴史  九州大学, 大学病院, 医員 (70380417)
加藤 秀則  九州大学, 大学病院, 講師 (60214392)
松田 貴雄  九州大学, 大学病院, 助手 (10304825)
有馬 隆博  九州大学, 生体防御医学研究所, 助手 (80253532)
Project Period (FY) 2002 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥113,230,000 (Direct Cost: ¥87,100,000、Indirect Cost: ¥26,130,000)
Fiscal Year 2006: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2005: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2004: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2003: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2002: ¥23,790,000 (Direct Cost: ¥18,300,000、Indirect Cost: ¥5,490,000)
KeywordsMolecular targeted Therapy / Cancer / senescence / Erα / MDM2 / p53 / p21 / HDAC inhibitor / proline hydroxylase / NECC1 / 絨毛細胞分化 / エストロゲン受容体α / 分子標的治療 / p21CDKインヒビター / ROS / lq42 / 細胞老化誘導遺伝子 / ERα / 活性型Ras / mdm2 / p53 / CDK結合領域
Research Abstract

A. We have cloned the NECCl gene from human chromosome 4 as a senescence inducing gene in choriocaracinoma cells. We investigated the placental anatomy of NECCl KO (-/-) mouse embryos. In the KO placeuta hypertrophy of giant cell layer and suppression of spongio-trophoblast layer formation were noticeable, respectively. NECCl expression was transiently detected in 8.5-11.5 dpc wild type mouse placenta. NECCl was involved in the negative regulation of differentiation from trophoblast stem cell to giant cell.
B. We have cloned the EGLNl gene that has the potential to induce endometrial cancer cell senescence from lg42 region. EGLNl was a member of prolyl hydroxylase family and regulated HIF1 α protein degradation. Inhibition of HIFl α-mediated signaling by FIH or HIFlsiRNA also induced the cancer cell senescence. Overexpression of EGLNl in endometrial cancer cells was able to induce cell senescence through upregulation of p21 CDK ihibitor.
C. We found the ER α activation by the oncogenic K-Ras mutant. Expression of PR or dominant-negative ER mutant elicited the cancer cell senescence. ER α inactivation resulted in the downregulation of MDM2 followed by p53 activation and subsequent p21 upregulation. We have demonstrated the efficacy of new therapies targetted i)functional inactivation of ER α and ii)suppression of MDM2 protein expression, respectively.
D. We have demonstrated the anti-tumor activity of Sodium Butyrate and Valproic acid that are HDAC inhibitors. Both agents were able to induce cancer cell senescence through p21 upregulation. This effect was independent of p53. Now we are planning the clinical research by using Valproic acid.

Report

(6 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (39 results)

All 2007 2006 2005 2004 Other

All Journal Article (26 results) Publications (13 results)

  • [Journal Article] Characterization of side population cells (SP cells) in human normal endometrial cells2007

    • Author(s)
      Kato K, Yoshimoto M, Kato K, Adachi S, Yamayoshi A, Arima T, Asanoma K, Kyo S, Nakahata T, Wake N
    • Journal Title

      Human Reproduction 22

      Pages: 1214-1223

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] An inhibitory effect on cell proliferation by blockage of the MAPK/Estrogen Receptor/MDM2 signal pathway in gynecologic cancer2007

    • Author(s)
      Suga S, Kato K, Yamayoshi A, Adachi S, Asanoma K, Yamaguchi S, Arima T, Kinoshita K, Wake N
    • Journal Title

      Gynecologic Oncology 105

      Pages: 341-350

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] An inhibitory effect on cell proliferation by blockage of the MAPK/Estrogen Receptor/MDM2 signal pathway in gynecologic cancer2007

    • Author(s)
      Suga S, KatoK, Yamayoshi A, Adachi S, Asanoma K, Yamaguchi S, Arima T, Kinoshita K, Wake N
    • Journal Title

      Gynecologic Oncology 105

      Pages: 341-350

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Characterization of side population cells (SP cells) in human normal endometrial cells2007

    • Author(s)
      kato K, Yoshimoto M, Kato K, Adachi S, Yamyoshi A, Arima T, Asanoma K, Kyo S, Nakahata T, Wake N
    • Journal Title

      Human Reproduction 22

      Pages: 1214-23

    • Related Report
      2006 Annual Research Report
  • [Journal Article] An inhibitory effect on cell proliferation by blockage of the MAPK / Estrogen Receptor / MDM2 signal pathway in gynecologic cancer2007

    • Author(s)
      Suga S, Kato K, Yamayoshi A, Adachi S, Asanoma K, Yamaguchi, Wake N.
    • Journal Title

      Gynecologic Oncology 105

      Pages: 341-350

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Induction of human endometrial cancer cell senescence through modulation of HIF-1α activity byEGLN12006

    • Author(s)
      Kato H, Inoue T, Asanoma K, Nishimura C, Matsuda T, Wake N
    • Journal Title

      International Journal of Cancer 118

      Pages: 1144-1153

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Activation of STAT3/5 Signal Pathways in Complete Mole and Repression in Choriocarcinoma Cell Lines2006

    • Author(s)
      Kato H, Inoue T, Asanoma K, Matsuda T, Yoshikawa Y, Wake N
    • Journal Title

      Journal of Reproductive Medicine 51

      Pages: 41-48

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Establishment of the primary imprint of the HYMAI/PLAGL1 imprint control region During oogenesis2006

    • Author(s)
      Arima T, Wake N
    • Journal Title

      Cytogenet Genome Res 113

      Pages: 247-252

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Adenovirus-Mediated Calponin h1 Gene Therapy Directed Against Peritoneal Dissemination of Ovarian Cancer : Bifunctional Therapeutic Effects on Peritoneal Cell Layerand Cancer Cells2006

    • Author(s)
      Ogura T, Kobayashi H, Ueoka Y, Okugawa K, Kato K, Hirakawa T, Hashimoto S, Taniguchi S, Hashimoto S, Wake N, Nakano H
    • Journal Title

      Clin Cancer Res 12(17)

      Pages: 5216-5223

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Adenovirus-Mediated Calponin h1 Gene Therapy Directed Against Peritoneal Dissemination of Ovarian Cancer : Bifunctional Therapeutic Effects on Peritoneal Cell Layer and Cancer Cells2006

    • Author(s)
      Ogura T, Kobayashi H, Ueoka Y, Okugawa K, Kato K, Hirakawa T, Hashimoto S, Taniguchi S, Hashimoto S, Wake N, Nakano H
    • Journal Title

      Clin Cancer Res 12(17)

      Pages: 5216-5223

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Induction of human endometrial cancer cell senescence through modulation of HIF-1α activity by EGLN12006

    • Author(s)
      Kato H, Inoue T, Asanoma K, Nishimura C, Matsuda T, Wake N
    • Journal Title

      International Journal of Cancer 118,

      Pages: 1144-1153

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Establishment of the primary imprint of the HYMAI/PLAGL1 imprint control region During oogenesis2006

    • Author(s)
      Arima T, Genome Res
    • Journal Title

      Cytogenet Genome Res 113

      Pages: 247-252

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Adenovirus-Mediated Calponin h1 Gene Therapy Directed against Peritoneal Dissemination of Ovarian Cancer : Bifunctional Therapeutic Effects on Peritoneal Cell Layer and Cancer Cells2006

    • Author(s)
      Ogura T, Kobayashi H, Ueoka Y, Okugawa K, Kato K, Hirakawa T, Hashimoto S, Taniguchi S, Hashimoto S, Wake N, Nakano H
    • Journal Title

      Clin Cancer Res 12(17)

      Pages: 5216-5223

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Induction of human endometrial cancer cell senescence through modulation of HIF-1α activity by EGLN12006

    • Author(s)
      Kato H
    • Journal Title

      International Journal of Cancer 118(5)

      Pages: 1144-1153

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Expression of progesterone receptor B is associated with G0/G1 arrest of the cell cycle and growth inhibition in NIH3T3 cells.2005

    • Author(s)
      Horiuchi S
    • Journal Title

      Exp Cell Res. 305(2)

      Pages: 233-243

    • Related Report
      2005 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.2005

    • Author(s)
      Kamikihara T
    • Journal Title

      International Journal of Cancer 115

      Pages: 690-700

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Zac, LIT1(KCNQ10T1) and p57KIP2(CDKN1C) are in an imprinted gene network which may play a role in Beckwith-Wiedemann Syndrome.2005

    • Author(s)
      Arima T
    • Journal Title

      Nucleic Acids Research 33;8

      Pages: 2650-2660

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Genetic origin and imprinting in hydatidiform moles. Comparison between DNA polymorphism analysis and immunoreactivity of p57KIP2.2005

    • Author(s)
      Kihara M
    • Journal Title

      Journal of reproductive Medicine 50(5)

      Pages: 307-312

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Differential diagnosis between complete and partial mole by TSSC3 antibody completely correlates to DNA diagnosis.2005

    • Author(s)
      Kato H
    • Journal Title

      Diagh Mol Pathol. 14(3)

      Pages: 164-169

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Genome-Wide Definitive Haplotypes Determined Using a Collection of Complete Hydatidiform Moles.2005

    • Author(s)
      Kukita Y
    • Journal Title

      Genome Research 15(11)

      Pages: 1511-1518

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Identification and characterization of two forms of mouse MUTYH proteins encoded by alternatively spliced transcripts.2004

    • Author(s)
      Ichinoe A et al.
    • Journal Title

      Nucl.Acids.Res. 32

      Pages: 477-487

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The parent-of-origin effect of 10q22 in pre-eclamptic females coincides with two regions clustered for genes with down-regulated expression in androgenetic placentas.2004

    • Author(s)
      Oudejans CB et al.
    • Journal Title

      Mol.Hum Reprod. 10(8)

      Pages: 589-598

    • Related Report
      2004 Annual Research Report
  • [Journal Article] K-Ras and H-Ras activation promote distinct consequences on endometrial cell survival. : 64,2759-2765(2004)2004

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

      Cancer Reserch 64

      Pages: 2759-2765

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Analysis of a candidate gene associated with growth suppression of choriocarcinoma and differentiation of trophoblasts.2004

    • Author(s)
      Asanoma K et al.
    • Journal Title

      J Reprod Med. 49(8)

      Pages: 617-626

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Expression of DOC and netrin-1 in normal human endometrium and its implication in endometrial carcinogenesis.2004

    • Author(s)
      Kato HD et al.
    • Journal Title

      Gynecol Oncol. 95(2)

      Pages: 281-289

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Retroperitoneal schwannoma bearing at the right vaginal wall.2004

    • Author(s)
      Inoue T et al.
    • Journal Title

      J Obstet Gynaecol Res. 30(6)

      Pages: 454-457

    • Related Report
      2004 Annual Research Report
  • [Publications] Asanoma K et al.: "NECC1, a candidate choriocarcinoma suppressor gene which encodes homeodomain consensus 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 disease with special reference to their clinical application"Best Practices & Research Clinical Obstetrics and Gynecology. 117. 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"Hum Mol Genet. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ninomiya et al.: "K-Ras and H-Ras activation promote distinct consequences on endometrial cell survival"Cancer Research. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kato K et al.: "Cell and Molecular Biology of Endometrial Carcinoma : Contribution of estrogen receptor α and progesterone receptor-β to oncogenic K-Ras-mediated NIH3T3 cell transformation"Springer-Verlag Tokyo. 207-218 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kato K et al.: "Contribution of estrogen receptora (ERα) to oncogenic K-Ras-mediated NIH3T3 cell transformation and its implication for escape from senescence by modulating the p53 pathway"Journal of Biological Chemistry. 277. 11217-11224 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kato H et al.: "Growth-associated Gene Expression Profiles by Microarray Analysis of Trophoblast of Molar Pregnancies and Normal Villi"International Journal of Gynecological Pathology. 21,3. 255-260 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Zhou Y et al.: "Identification of FOXC1 as a TGF-β1 responsive gene and its involvement in negative regulation of cell growth"Genomics. 80,5. 465-472 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Asanoma K et al.: "NECC1, a candidate choriocarcinoma suppressor gene which encodes homeodomain consensus motif"Genomics. (in press).

    • Related Report
      2002 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. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Kato K et al.: "Cell and Molecular Biology of Endometrial Carcinoma, Springer-Verlag Tokyo"Contribution of estrogen receptor α and progesterone receptor-B to oncogenic K-Ras-mediated NIH3T3 cell transformation. (in press).

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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