| Project/Area Number |
15390503
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 | Nagoya University |
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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)
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| 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)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| 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)
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| Keywords | Oxytocinase / Aminopeptidase / Oxytocin / Endometrial Cancer / Trophoblast / Transcription Factor / Differentiation / invasion |
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| 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.
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