New Development of Oxytocinase Study to Spread through Gynecologic Tumors

催产素通过妇科肿瘤传播的研究新进展

• 批准号: 15390503
• 负责人: NOMURA Seiji
• 金额: $ 4.93万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390503/
• 关键词: Oxytocinase; Aminopeptidase; Oxytocin; Endometrial Cancer; Trophoblast; Transcription Factor; Differentiation; invasion

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.

胎盘亮氨酸氨肽酶（P-aminopeptidase，P-aminopeptidase）是目前已知唯一能降解催产素（oxytocin，OT）的膜氨肽酶。本研究旨在探讨P-LAP与妇科癌症的可能关系。我们发现，P-LAP转染的子宫内膜癌细胞不仅从OT诱导的生长抑制中部分恢复，而且在没有OT的条件下显示出比亲代细胞更高的生长速度。在子宫内膜样腺癌组织中P-gp强阳性染色的患者中，无病间期显著低于P-gp阴性或弱阳性染色的患者。此外，我们已经证明，P-gp表达与子宫内膜癌患者的化疗敏感性有关。体外实验结果表明，P-CRP在子宫内膜癌细胞中的过表达导致了对紫杉醇和卡铂的化疗耐药，而P-CRP的下调则增强了对紫杉醇和卡铂的化疗敏感性，这种作用可能是通过抑制P-CRP相关的凋亡而介导的。除了我们先前的发现，即P-β 1在分化的合体滋养细胞中表达，以及转录因子AP-2和Ikaros参与P-β 1的表达外，我们已经发现AP-2α亚型调节P-gp的分化依赖性表达。我们还证实了AP-2α在体外抑制卵巢癌细胞的侵袭，并且腹腔注射AP-2α过表达细胞的裸鼠比新转染细胞的裸鼠存活时间更长。在Ikaros亚型中，Ikaros-x主要表达于绒毛外滋养层细胞（EVT），并参与EVT的迁移和侵袭。

项目成果

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).

Nomura S、Ito T、Mizutani S：“胎盘亮氨酸氨肽酶。生物学和疾病中的蛋白酶系列第 2 卷“生物学和疾病中的氨肽酶”“Kluwer plenum（正在印刷中）。

Regulation of aminopeptidase A expression in cervical carcinoma : role of tumor-stromal interaction and vascular endothelial growth factor.

宫颈癌中氨肽酶 A 表达的调节：肿瘤-基质相互作用和血管内皮生长因子的作用。

• 发表时间: 2004
• 期刊: Lab Invest 84
• 作者: Kikkawa F et al.;Morita T et al.;Kikkawa F et al.;Ino K et al.;Shibata K et al.;Mizokami Y et al.;Suganuma T et al.
• 通讯作者: Suganuma T et al.

Cystinyl aminopeptidase, oxytocinase and insulin-regulated aminopeptidas. In Handobook of Proteolytic enzymes, 2nd edition

胱氨酰氨肽酶、催产素酶和胰岛素调节氨肽。

• 发表时间: 2004
• 作者: S Nomura;et al.
• 通讯作者: et al.

Role of aminopeptidases in the blood pressure regulation

氨肽酶在血压调节中的作用

• 发表时间: 2004
• 期刊: Biol Pharm Bull 27
• 作者: Mitsui T;et al.
• 通讯作者: et al.

Placental leucine aminopeptidase. In Proteases in Biology and Disease series, vol. 2 "Aminopeptidases in Biology and Disease".

胎盘亮氨酸氨肽酶。

• 发表时间: 2004
• 作者: S Nomura;et al.
• 通讯作者: et al.