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

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。

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.