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New Development of Oxytocinase Study to Spread through Gynecologic Tumors

Research Project

Project/Area Number 15390503
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Obstetrics and gynecology
Research InstitutionNagoya University

Principal Investigator

NOMURA Seiji (2004-2005)  Nagoya University, Graduate School of Medicine, Associate Professor, 大学院・医学系研究科, 助教授 (20242860)

水谷 榮彦 (2003)  名古屋大学, 大学院・医学系研究科, 教授 (00159162)

Co-Investigator(Kenkyū-buntansha) KIKKAWA Fumitaka  Nagoya University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (40224985)
野村 誠二  名古屋大学, 大学院・医学系研究科, 助教授 (20242860)
Project Period (FY) 2003 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥7,700,000 (Direct Cost: ¥7,700,000)
Fiscal Year 2005: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2004: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2003: ¥5,100,000 (Direct Cost: ¥5,100,000)
KeywordsOxytocinase / Aminopeptidase / Oxytocin / Endometrial Cancer / Trophoblast / Transcription Factor / Differentiation / invasion
Research Abstract

Placental leucine aminopeptidase (P-LAP) is the only membrane aminopeptidase known to functionally degrade oxytocin (OT) as oxytocinase. This study aimed to investigate the possible involvement of P-LAP in gynecologic cancers.
We have shown that P-LAP-transfectant endometrial cancer cells not only partially recovered from OT-induced growth inhibition but also showed a higher growth rate than parental cells under condition without OT. In patients who had strongly positive P-LAP staining in their endometrial endometrioid adenocarcinoma tissues, the disease-free interval was significantly lower than in patients who had negative or weakly positive P-LAP staining. In addition, we have demonstrated that P-LAP expression was associated with chemosensitivity in endometrial carcinoma patients. Also in vitro, overexpression of P-LAP in endometrial carcinoma cells resulted in the chemoresistance to paclitaxel and carboplatin, while P-LAP downregulation enhanced the chemosensitivity, which would be mediated via inhibition of mitochondria-related apoptosis.
In ovarian tumors, P-LAP expression was increased in order of benign, borderline and malignant tumors, which was co-related with GLUT4 expression.
In addition to our previous findings that P-LAP is expressed in differentiated syncytiotrophoblasts and that transcriptional factors AP-2 and Ikaros are involved in P-LAP expression, we have found that AP-2α isoform regulated differentiation-dependent expression of P-LAP. We have also demonstrated that AP-2α suppressed invasion of ovarian carcinoma cells in vitro and that nude mice intraperitoneally injected with AP-2α-overexpressing cells survived longer than those with neo-transfected cells. Among the Ikaros isoforms, Ikaros-x was predominantly expressed in extravillous trophoblasts (EVTs) and involved in the migration and invasion of EVTs.

Report

(4 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (54 results)

All 2006 2005 2004 2003 Other

All Journal Article (42 results) Book (5 results) Publications (7 results)

  • [Journal Article] Ikaros is expressed in human extravillous trophoblasts and involved in their migration and invasion2006

    • Author(s)
      Yamamoto E, et al.
    • Journal Title

      Mol Human Reprod (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Ikaros is expressed in human extravillous trophoblasts and involved in their migration and invasion.2006

    • Author(s)
      Yamamoto E, et al.
    • Journal Title

      Mol Human Reprod (in press)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Possible involvement of aminopeptidase A in hypertension and renal damage in Dahl salt-sensitive rats2005

    • Author(s)
      Nomura M, et al.
    • Journal Title

      Am J Hypertens 18

      Pages: 538-543

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Possible involvement of adipocyte-derived leucine aminopeptidase via angiotensin II in endometrial carcinoma.2005

    • Author(s)
      Shibata K, et al.
    • Journal Title

      Tumor Biol 26

      Pages: 9-16

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Placental leucine aminopeptidase (P-LAP) and glucose transporter 4 (GLUT4) expression in benign, borderline, and malignant ovarian epithelia2005

    • Author(s)
      Shibata K, et al.
    • Journal Title

      Gynecol Oncol 98

      Pages: 11-18

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Gene regulation and physiological function of placental leucine aminopeptidase/oxytocinase during pregnancy.2005

    • Author(s)
      Nomura S, et al.
    • Journal Title

      BBA-Proteins and Proteomics 1751

      Pages: 19-25

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Dipeptidyl peptidase IV in tumor progression2005

    • Author(s)
      Kikkawa F, et al.
    • Journal Title

      BBA-Proteins and Proteomics 1751

      Pages: 45-51

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A novel role for placental leucine aminopeptidase (P-LAP) as a determinant of chemoresistance in endometrial carcinoma cells2005

    • Author(s)
      Kondo C, et al.
    • Journal Title

      Int J Cancer 118

      Pages: 1390-1394

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Possible involvement of aminopeptidase A in hypertension and renal damage in Dahl salt-sensitive rats2005

    • Author(s)
      Nomura M, et al.
    • Journal Title

      Am J Hypertens, 18

      Pages: 538-543

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Posibble involvement of adipocyte-derived leucine aminopeptidase via angiotensin II in endometrial carcinoma.2005

    • Author(s)
      Shibata K, et al.
    • Journal Title

      Tumor Biol, 26

      Pages: 9-16

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Placental leucine aminopeptidase (P-LAP) and glucose transporter 4 (GLUT4) expression in benign, borderline, and malignant ovarian epithelia2005

    • Author(s)
      Shibata K, et al.
    • Journal Title

      Gynecol Oncol, 98

      Pages: 11-18

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Gene regulation and physiological function of placental leucine aminopeptidase/oxytocinase during pregnancy2005

    • Author(s)
      Nomura S, et al.
    • Journal Title

      BBA-Proteins and Proteomics 1751

      Pages: 19-25

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] A novel role for placental leucine aminopeptidase (P-LAP) as a determinant of chemoresistance in endometrial carcinoma cells.2005

    • Author(s)
      Kondo C, et al.
    • Journal Title

      Int J Cancer 118

      Pages: 1390-1394

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Dipeptidyl peptidase IV in tumor progression2005

    • Author(s)
      Kikkawa F, et al.
    • Journal Title

      BBA - Proteins and Proteomics 1751

      Pages: 45-51

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Gene regulation and physiological function of placental leucine aminopeptidase/oxytocinase during pregnancy2005

    • Author(s)
      Nomura S, et al.
    • Journal Title

      BBA - Proteins and Proteomics 1751

      Pages: 19-25

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Placental leucine aminopeptidase (P-LAP) and glucose transporter 4 (GLUT4) expression in benign, borderline, and malignant ovarian epithelia.2005

    • Author(s)
      Shibata K, et al.
    • Journal Title

      Gynecol Oncol 98

      Pages: 11-18

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Possible involvement of adipocyte-derived leucine aminopeptidase via angiotensin II in endometrial carcinoma2005

    • Author(s)
      Shibata K, et al.
    • Journal Title

      Tumor Biol 26

      Pages: 9-16

    • Related Report
      2005 Annual Research Report
  • [Journal Article] ADAMs, a disintegrin and metalloproteinases, mediate shedding of oxytocinase.2004

    • Author(s)
      Ito N, et al.
    • Journal Title

      Biochem Biophys Res Commun 314

      Pages: 1008-1013

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Insulin stimulates placental leucine aminopeptidase/oxytocinase/insulin-regulated membrane aminopeptidase expression in BeWo choriocarcinoma cells2004

    • Author(s)
      Nakata M, et al.
    • Journal Title

      Regul Pept. 117

      Pages: 187-193

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Tissue distribution of placental leucine aminopeptidase/oxytocinase during mouse pregnancy2004

    • Author(s)
      Kobayashi H, et al.
    • Journal Title

      J Histochem Cytochem 52

      Pages: 113-122

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Regulation of aminopeptidase A expression in cervical carcinoma : Role of tumor-stromal interaction and vascular endothelial growth factor2004

    • Author(s)
      Suganuma T, et al.
    • Journal Title

      Lab Invest 84

      Pages: 639-648

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Signal pathway involved in increased expression of neutral endopeptidase 24.11 by gonadotropin releasing hormone in choriocarcinoma cells2004

    • Author(s)
      Kikkawa F, et al.
    • Journal Title

      Placenta 25

      Pages: 176-183

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Expression of placental leucine aminopeptidase (P-LAP) is associated with poor outcome in endometrial endometrioid adenocarcinoma2004

    • Author(s)
      Shibata K, et al.
    • Journal Title

      Oncology 66

      Pages: 288-295

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Activation of invasiveness of cervical carcinoma cells by angiotensin II.2004

    • Author(s)
      Kikkawa F, et al.
    • Journal Title

      Am J Obstet Gynecol. 190

      Pages: 1258-1263

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Possible involvement of placental peptidases that degrade gonadotropireleasing horomone (GnRH) in the dynamic pattern of placental hCG secretion via GnRH degradation2004

    • Author(s)
      Kikkawa F, et al.
    • Journal Title

      Placenta 23

      Pages: 483-489

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Suppression of invasion and peritoneal carcinomatosis of ovarian cancer cells by overexpression of AP-2alpha2004

    • Author(s)
      Sumigama S, et al.
    • Journal Title

      Oncogene 23

      Pages: 5496-5504

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Placental leucine aminopeptidase (P-LAP) expression is associated with chemosensitivity in human endometrial carcinoma2004

    • Author(s)
      Shibata K, et al.
    • Journal Title

      Gynecol Oncol 95

      Pages: 307-313

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Role of aminopeptidases in the blood pressure regulation2004

    • Author(s)
      Mitsui T, et al.
    • Journal Title

      Biol Pharm Bull 27

      Pages: 768-771

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Regulation of aminopeptidase A expression in cervical carcinoma : Role of tumor-stromal interaction and vascular endothelial growth factor2004

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

      Lab Invest 84

      Pages: 639-648

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Activation of invasiveness of cervical carcinoma cells by angiotensin II.2004

    • Author(s)
      Kikkawa F, et al.
    • Journal Title

      Am J Obstet Gynecol 190

      Pages: 1258-1263

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Possible involvement of placental peptidases that degrade gonadotropireleasing horomone (GnRH) in the dynamic pattern of placental hCG secretion via GnRH degradation2004

    • Author(s)
      Kikkawa F, et al.
    • Journal Title

      Placenta, 23

      Pages: 483-489

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Suppression of invasion and peritoneal carcinomatosis of ovarian cancer cells by overexpression of AP-2alpha2004

    • Author(s)
      Sumigama S, et al.
    • Journal Title

      Oncogene, 23

      Pages: 5496-5504

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Role of aminopeptidases in the blood pressure regulation2004

    • Author(s)
      Mitsui T, et al.
    • Journal Title

      Biol Pharm Bull, 27

      Pages: 768-771

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Regulation of aminopeptidase A expression in cervical carcinoma : Role of tumor-stromal interaction and vascular endothelial growth factor.2004

    • Author(s)
      Suganuma T, et al.
    • Journal Title

      Lab Invest 84

      Pages: 639-648

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Signal pathway involved in increased expression of neutral endopeptidase 24.11 by gonadotropin releasing hormone in choriocarcinoma cells.2004

    • Author(s)
      Kikkawa F, et al.
    • Journal Title

      Placenta 25

      Pages: 176-183

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Suppression of invasion and peritoneal carcinomatosis of ovarian cancer cells by overexpression of AP-2alpha.2004

    • Author(s)
      Sumigama S, et al.
    • Journal Title

      Oncogene 23

      Pages: 5496-5504

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Placental leucine aminopeptidase (P-LAP) expression is associated with chemosensitivity in human endometrial carcinoma.2004

    • Author(s)
      Shibata k, et al.
    • Journal Title

      Gynecol Oncol 95

      Pages: 307-313

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Role of aminopeptidases in the blood pressure regulation.2004

    • Author(s)
      Mitsui T, et al.
    • Journal Title

      Biol Pharm Bull 27

      Pages: 768-771

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Placental leucine aminopeptidase/oxytocinase gene regulation by activator protein-2 in BeWo cell model of human trophoblast differentiation.2003

    • Author(s)
      Iwanaga K, et al.
    • Journal Title

      FEBS Lett 552

      Pages: 120-124

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Expression of adipocyte-derived leucine aminopeptidase in endometrial cancer : association with tumor grade and CA-125.2003

    • Author(s)
      Kazeto H, et al.
    • Journal Title

      Tumor biol 24

      Pages: 203-208

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Placental leucine aminopeptidase/oxytocinase gene regulatio by activator protein-2 in BeWo cell model of human trophoblast differentiation.2003

    • Author(s)
      Iwanaga K, et al.
    • Journal Title

      FEBS Lett 552

      Pages: 120-124

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Expression of adipocyte-derived leucine aminopeptidase in endometrial cancer : association with tumor grade and CA-1252003

    • Author(s)
      Kazeto H, et al.
    • Journal Title

      Tumor biol 24

      Pages: 203-208

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] Placental leucine aminopeptidase. In Proteases in Biology and Disease series, vol. 2 "Aminopeptidases in Biology and Disease".2004

    • Author(s)
      S Nomura, et al.
    • Total Pages
      354
    • Publisher
      Kluwer plenum
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] Crystinyl aminopeptidase, oxytocinase and insulin-regulated aminopeptidase. In Handobook of Proteolytic enzymes, 2nd edition2004

    • Author(s)
      S Nomura, et al.
    • Total Pages
      2368
    • Publisher
      Academic Press, Elsevier Science
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] Placental leucine aminopeptidase. In Proteases in Biology and Disease series, vol.2 "Aminopeptidases in Biology and Disease".2004

    • Author(s)
      S Nomura, et al.
    • Total Pages
      354
    • Publisher
      Kluwer plenum
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] Cystinyl aminopeptidase, oxytocinase and insulin-regulated aminopeptidas. In Handobook of Proteolytic enzymes, 2nd edition2004

    • Author(s)
      S Nomura, et al.
    • Total Pages
      2368
    • Publisher
      Academic Press, Elsevier Science
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] Handbook of Proteolitic enzymes, 2nd edition (Cystinyl aminopeptidase, oxytocinase and insulin-regulated aminopeptidase.)2004

    • Author(s)
      Nomura S, Tsujimoto M, Mizutani S
    • Publisher
      Academic Press, Elsevier Science
    • Related Report
      2004 Annual Research Report
  • [Publications] Shibata K, Kikkawa F, Nomura S, Mizutani S et al.: "Expression of placental leucine aminopeptidase (P-LAP) is associated with poor outcome in endometrial endometorioid adenocarcinoma"Oncology. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Nakata M, Nomura S, Kikkawa F, Mizutani S et al.: "Insulin stimulates placental leucine aminopeptidase/oxytocinase/insulin-regulated membrane aminopeptidase expression in BeWo choriocarcin"Regul Pept. 117. 187-193 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ito N, Nomura S, Kikkawa F, Mizutani S et al.: "ADAMs, a disintegrin and metalloproteinases, mediate shedding of oxytocinase"Biochem Biophys Res Commun. 314. 1008-1013 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Suzuki Y, Kikkwa F, Nomura S, Mizutani S et al.: "Possible role of placental leucine aminopeptidase in the antiproliferative effect of oxytocin in human endometrial adenocarcinoma"Clin Cancer Res. 9. 1528-1534 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Iwanaga K, Nomura S, Kikkawa F, Mizutani S et al.: "Placental leucine aminopeptidase/oxytocinase Rene regulation by activator protein-2 in BeWo cell model of human trophoblast differentiatio"FEBS lett. 552. 120-124 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ino K, Kikkawa F, Nomura S, Mizutani S et al.: "Expression of placental leucine aminopeptidase and adipocyte-derived leucine aminopeptidase in human normal and malignant invasive trophoblastic cells"Lab invest. 87. 1799-1809 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nomura S, Ito T, Mizutani S: "Placental leucine aminopeptidase. In Proteases in Biology and Disease series vol. 2"Aminopeptidases in Biology and Disease""Kluwer plenum(in press).

    • Related Report
      2003 Annual Research Report

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

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