New Development of Oxytocinase Study to Spread through Gynecologic Tumors

胎盘亮氨酸氨基肽酶(P-LAP)是目前已知的唯一一种功能降解催产素(OT)的膜型氨基肽酶。本研究旨在探讨P-LAP在妇科肿瘤中的可能作用。我们发现，在没有OT的条件下，转导P-LAP的子宫内膜癌细胞不仅部分地从OT诱导的生长抑制中恢复过来，而且表现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-LAP染色强阳性的患者，其无病间期显著低于P-LAP染色阴性或弱阳性的患者。此外，我们还证明了P-LAP的表达与子宫内膜癌患者的化疗敏感性有关。同样在体外，P-LAP在子宫内膜癌细胞中的过表达导致对紫杉醇和卡铂的化疗耐药，而P-LAP的下调增强了对化疗的敏感性，这可能是通过抑制线粒体相关的凋亡来实现的。在卵巢肿瘤中，P-LAP的表达按良性、交界性和恶性肿瘤的顺序递增，这与Glut4的表达密切相关。除了我们之前的发现，P-LAP在分化的合体滋养层细胞中表达，转录因子AP-2和Ikaros参与P-LAP的表达外，我们还发现AP-2α亚型调节P-LAP的分化依赖性表达。我们还证明了AP-2α在体外能抑制卵巢癌细胞的侵袭，并且在裸鼠体内注射过表达AP-2α的细胞比新基因转染组的裸鼠存活时间长。在Ikaros亚型中，Ikaros-x主要表达于绒毛外滋养层细胞，参与绒毛外滋养层细胞的迁移和侵袭。

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.