New Development of Oxytocinase Study to Spread through Gynecologic Tumors

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-STAT在妇科肿瘤中的可能作用，我们发现P-STAT转染的子宫内膜癌细胞不仅部分恢复了OT诱导的生长抑制，而且在无OT的条件下显示出比亲本细胞更高的生长速率。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。

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.