Neutral endopeptidase 24.11/CD10 suppresses progressive potential in ovarian carcinoma in vitro and in vivo
Neutral endopeptidase 24.11/CD10 suppresses progressive potential in ovarian carcinoma in vitro and in vivo
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DOI：
10.1158/1078-0432.ccr-04-2395
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发表时间：
2005-03-01
影响因子：
11.5
通讯作者：
Kikkawa, F
中科院分区：
文献类型：
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作者：
Kajiyama, H;Shibata, V;Kikkawa, F
近年来，大量研究表明，内皮素-1（ET-1）在卵巢癌中表达，并且ET-1通过内皮素A受体（ETAR）选择性地作为自分泌或旁分泌生长因子，并参与细胞增殖、侵袭、新生血管形成和防止细胞凋亡。中性内肽酶24.11（Neutral endopeptidase 24.11，NEP）是一种广泛表达的细胞表面氨肽酶，能够降解包括ET-1在内的多种生物活性肽。我们以前的研究表明，卵巢癌间质NEP表达随组织学分级的增高而下调。在此，我们证实了NEP在卵巢癌的肿瘤细胞以及间质组织中表达，并研究了NEP在卵巢癌中的功能。我们发现，有一个显着的细胞增殖和侵袭能力的降低，在条件培养基中的ET-1的浓度降低对卵巢癌细胞中NEP的过表达。此外，NEP的过度表达增强了对紫杉醇的敏感性，导致凋亡形态学改变的发生增加。此外，肿瘤发生减少在体内与过度表达的NEP，下调基质金属蛋白酶-2，血管内皮生长因子的表达。这一证据表明，NEP功能抑制卵巢癌的进展，这种酶的进一步研究可能会揭示一个有效的方法来靶向ET-1治疗这种癌症。
Recently, numerous studies have shown that endothelin-1 (ET-1) is expressed in ovarian carcinoma and that ET-1 selectively acts as an autocrine or paracrine growth factor through the endothelin A receptor (ETAR), and is involved in cell proliferation, invasiveness, neovascularization, and prevention of apoptosis. Neutral endopeptidase 24.11 (NEP) is a cell surface aminopeptidase with a ubiquitous expression and is capable of degrading a number of bioactive peptides including ET-1. Our previous report showed that stromal NEP expression in ovarian carcinoma was down-regulated as the histologic grade advanced. Here, we confirmed that NEP was expressed in tumor cells as well as stromal tissues in ovarian carcinoma, and investigated the functions of NEP in this carcinoma. We showed that there was a significant decrease in cell proliferation and invasiveness with a reduction in the concentration of ET-1 in the conditioned medium on the overexpression of NEP in ovarian carcinoma cells. In addition, the overexpression of NEP enhanced susceptibility to paclitaxel, resulting in an increased occurrence of apoptotic morphologic change. Furthermore, tumorigenesis was reduced in vivo with the overexpression of NEP, down-regulation of both matrix metalloproteinase-2, and vascular endothelial growth factor expression. This evidence suggests that NEP functionally suppresses the progression of ovarian carcinoma and further study of this enzyme may reveal an effective way to target ET-1 for the treatment of this carcinoma.