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Expression and function of cell-surface peptidases in gynecologic cancers and suppression of tumor progression by the targeted therapy against these peptidases

细胞表面肽酶在妇科癌症中的表达和功能以及针对这些肽酶的靶向治疗抑制肿瘤进展

基本信息

批准号：
15591742
负责人：
INO Kazuhiko
金额：
$ 1.92万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
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

项目摘要

In the present study, we examined the expression and function of the four cell-surface peptidases, aminopeptidase A (APA), neutral endopeptidase (NEP), dipeptidyl peptidase IV (DPPIV), and placental leucine aminopeptidase (P-LAP) in gynecologic cancer cells. APA, NEP, DPPIV and P-LAP were differentially expressed and localized in various gynecologic malignancies including cervical cancer, endometrial cancer, ovarian cancer and choriocarcinoma in a tumor-type specific pattern. The expression levels were up-regulated or down-regulated depending on histological grade or disease progression. These peptidases play regulatory roles in tumor cell proliferation, migration, invasion or angiogenesis via degradation/inactivation of target peptides such as angiotensin II, endothelin-1, some chemokines (e.g. SDF-1,RANTES) and oxytocin, which act on cancer cells as a stimulatory or inhibitory factor. Our in vivo studies using nude mouse xenograft models demonstrated that overexpression of APA, NEP or DPPIV suppressed the growth, metastasis, angiogenesis, and peritoneal dissemination of ovarian cancer or cervical cancer. In contrast, P-LAP overezpression in endometrial cancer significantly correlated with impaired patient prognosis and the resistance of cancer cells to chemotherapy. In conclusion, these peptidases may become not only a new diagnostic/prognostic marker, but also a novel molecular target for treatment of gynecologic malignancies.

在本研究中，我们研究了四种细胞表面肽酶的表达和功能，氨肽酶A（阿帕），中性内肽酶（NEP），二肽基肽酶IV（DPPIV），和胎盘亮氨酸氨肽酶（P-PAPIV）在妇科癌细胞。阿帕、NEP、DPPIV和P-CRP在宫颈癌、子宫内膜癌、卵巢癌和绒毛膜癌等多种妇科恶性肿瘤组织中的表达存在差异，并具有肿瘤类型特异性。表达水平上调或下调取决于组织学分级或疾病进展。这些肽酶通过降解/失活靶肽如血管紧张素II、内皮素-1、一些趋化因子（例如SDF-1、RANTES）和催产素（其作为刺激或抑制因子作用于癌细胞）在肿瘤细胞增殖、迁移、侵袭或血管生成中发挥调节作用。我们在裸鼠异种移植模型中的体内研究表明，阿帕，NEP或DPPIV的过表达抑制卵巢癌或宫颈癌的生长，转移，血管生成和腹膜播散。相反，子宫内膜癌中P-gp的过度表达与患者预后受损和癌细胞对化疗的抵抗显著相关。总之，这些肽酶不仅可能成为一种新的诊断/预后标志物，而且可能成为治疗妇科恶性肿瘤的新的分子靶点。

项目成果

期刊论文数量（112）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Stromal cell-derived factor-1alpha-induced cell proliferation and its possible regulation by CD26/dipeptidyl peptidase IV in endometrial adenocarcinoma.

子宫内膜腺癌中基质细胞衍生因子 1α 诱导的细胞增殖及其可能受 CD26/二肽基肽酶 IV 的调节。

DOI：
发表时间：
2004
期刊：
Int J Cancer 110
影响因子：
0
作者：
Shibata K;et al.;Ino K et al.;Shibata K et al.;Mizokami Y et al.;Kikkawa F et al.;Mizokami Y et al.
通讯作者：
Mizokami Y et al.

Kluwer Academic/Plenum Publishers,New York

克鲁沃学术/全会出版社，纽约