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，我们检测了四种细胞表面肽酶：氨基肽酶A(APA)、中性内肽酶(NEP)、二肽基肽酶IV(DPPIV)和胎盘亮氨酸氨基肽酶(P-LAP)在妇科癌细胞中的表达和功能。APA、NEP、DPPIV和P-LAP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中有不同的表达和定位。表达水平的上调或下调取决于组织学分级或疾病进展。这些多肽酶通过降解/失活靶分子如血管紧张素II、内皮素-1、某些趋化因子(如SDF-1、RANTES)和催产素来调节肿瘤细胞的增殖、迁移、侵袭或血管生成，这些多肽作为刺激或抑制因子作用于肿瘤细胞。我们使用裸鼠移植瘤模型进行的体内研究表明，过表达APA、NEP或DPPIV可以抑制卵巢癌或宫颈癌的生长、转移、血管生成和腹膜转移。相反，子宫内膜癌中P-LAP的过度表达与患者预后不良和癌细胞对化疗的耐药性显著相关。综上所述，这些多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.