Anti-Progressive Effect of Neutral Endopeptidase 24.11 (NEP/CD10) on Cervical Carcinoma in vitro and in vivo
Anti-Progressive Effect of Neutral Endopeptidase 24.11 (NEP/CD10) on Cervical Carcinoma in vitro and in vivo
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DOI：
10.1159/000087476
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发表时间：
2005-08
期刊：
影响因子：
3.5
通讯作者：
Mikio Terauchi;H. Kajiyama;K. Shibata;K. Ino;S. Mizutani;F. Kikkawa
中科院分区：
文献类型：
--
作者：
Mikio Terauchi;H. Kajiyama;K. Shibata;K. Ino;S. Mizutani;F. Kikkawa
目的：已知中性内肽酶24.11（NEP）通过酶促失活生物活性肽如内皮素-1（ET-1）、血管紧张素-II和铃蟾肽在维持体内平衡或在某些人类恶性肿瘤的肿瘤转化和肿瘤进展中发挥重要作用。方法：本研究首先采用免疫组化和Western blot方法检测NEP在宫颈癌中的表达。接下来，我们通过产生NEP过表达的宫颈癌细胞来检查NEP在体外和体内的功能。结果如下：我们发现，在宫颈癌CaSki细胞中，具有ET-1自分泌环的NEP过表达在条件培养基中降低ET-1浓度，细胞增殖和侵袭能力显著降低。此外，通过用特异性抑制剂阻断NEP活性，这些电位被取消。虽然载体转染的CaSki细胞甚至可以在无血清培养基中生长，但NEP过表达细胞在这些培养基中未能增殖。此外，我们证明，NEP抑制裸鼠皮下异种移植瘤的形成。结论：我们的研究结果表明，NEP作为一种抑癌基因在宫颈癌细胞中发挥作用，其表达可能具有预后意义。进一步阐明NEP的作用机制将有助于更好地理解其在宫颈癌病理生理学中的作用。
Objectives: Neutral endopeptidase 24.11 (NEP) is known to play important roles in the maintenance of homeostasis or in neoplastic transformation and tumor progression in certain human malignancies through the enzymatic inactivation of bioactive peptides such as endothelin-1 (ET-1), angiotensin-II, and bombesin. Methods: In this study, we first investigated NEP expression in cervical carcinoma by immunohistochemical staining and Western blot analysis. Next, we examined NEP functions in vitro and in vivo by generating NEP-overexpressing cervical carcinoma cells. Results: We found a significant decrease in cellular proliferative and invasive abilities with a reduced ET-1 concentration in the conditioned medium by NEP overexpression in cervical carcinoma CaSki cells, which have an ET-1 autocrine loop. In addition, these potentials were cancelled by blockade of NEP activity with a specific inhibitor. Although vector-transfected CaSki cells could grow even in serum-free media, NEP-overexpressing cells failed to proliferate in these media. Furthermore, we demonstrated that NEP suppressed tumor formation of subcutaneous xenografts using nude mice. Conclusions: Our results indicated that NEP functions as a tumor-suppressor gene in cervical carcinoma cells, and its expression may have prognostic significance. Further elucidation of the mechanism underlying the observed effect of NEP will contribute to a better understanding of its role in the pathophysiology of cervical carcinoma.