促性腺激素释放激素（gonadotropin-releasing hormone,GnRH）是由下丘脑合成的十肽激素，主要功能是控制卵泡刺激素(FSH)和黄体生成素(LH)的释放，在性别分化、性腺发育以及生殖过程中起重要调节作用。迄今为止，在人体内发现存在GnRH-I和GnRH-II两种亚型。已有证据表明，GnRH-I和GnRH-II除了在内分泌系统中发挥核心作用外，还可直接作用于人胎盘的滋养层细胞，促进滋养层细胞侵润母体子宫，在胎盘发生、建立母胎循环的过程中发挥作用。这两种GnRH亚型在调节滋养层细胞侵润行为时却表现出不同的效应，而关于二者发挥作用的信号通路以及不同效应的分子机制尚不知晓。
中国科学院动物研究所王雁玲研究员领导的研究组与加拿大英属哥伦比亚大学Peter C.K. Leung教授的研究组合作，利用原代培养的人滋养层细胞作为研究模型，对GnRH-I和GnRH-II作用的分子机制进行了深入研究。结果发现，GnRH-I和GnRH-II都能通过激活PKC、ERK和JNK激酶调节滋养层细胞的侵润，但是GnRH-II是通过转导激活EGF受体酪氨酸激酶活性实现上述激酶的激活，而GnRH-I的作用是EGF受体非依赖型的。利用RNA干扰技术敲除I型GnRH受体，只有GnRH-I的促侵润作用被阻断，而对GnRH-II的作用没有显著影响，表明可能存在新的特异性的GnRH-II受体。该研究首次揭示了人胎盘中GnRH-I和GnRH-II通过不同的受体和信号交联通路调节细胞侵润行为，而这种配体依赖性选择信号通路的机制对于理解不同亚型GnRH在垂体外组织中的生理功能具有重要意义。
以上研究成果最近发表于内分泌学国际权威学术期刊 Molecular Endocrinology (Liu J, MacCalman CD, Wang YL, Leung PC. Molecular Endocrinology. 2009, 23(7):1014-1021)。第一作者刘璟为生殖病理研究组2007年毕业的博士研究生，通讯作者王雁玲为生殖病理研究组组长。这一工作受到国家重大科学研究计划课题(No. 2006CB944008) 和中科院知识创新工程重要方向性项目(Grant No. KSCX2-YW-R-53)资助。（生物谷Bioon.com）
生物谷国庆专题：新中国生命科学60年
生物谷推荐原始出处：
Molecular Endocrinology, doi:10.1210/me.2008-0451
Promotion of Human Trophoblasts Invasion by Gonadotropin-Releasing Hormone (GnRH) I and GnRH II via Distinct Signaling Pathways
Jing Liu, Colin D. MacCalman, Yan-ling Wang and Peter C. K. Leung
State Key Laboratory of Reproductive Biology (J.L., Y.-l.W.), Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, People’s Republic of China; and Department of Obstetrics and Gynecology (J.L., C.D.M., P.C.K.L.), University of British Columbia, Vancouver, British Columbia, Canada V6H 3V5
The potential roles of GnRH I and GnRH II have been assigned in promoting the invasive capacity of human trophoblasts by regulating matrix metalloproteinases-2 and -9, type I tissue inhibitor of matrix metalloproteinase, and urokinase plasminogen activator/plasminogen activator inhibitor protease systems during human placentation, and GnRH II has been shown to be more potent than GnRH I. However, the mechanisms for the differential effects of these two hormones remain unclear. In this study, we examined the invasion-promoting effects and the signaling pathways of GnRH I and GnRH II in human trophoblasts. The data revealed that both GnRH I and GnRH II were key autocrine and/or paracrine regulators in facilitating trophoblast invasion. The GnRH receptor antagonist (Antide) and specific small interfering RNA for GnRH receptor inhibited the regulatory effects of GnRH I, but not GnRH II, on trophoblast invasion. Both GnRH I and II activated protein kinase C, ERK1/2, and c-Jun N-terminal kinase to mediate their effects on trophoblast invasion, whereas only GnRH II elicited invasion-promoting action through transactivating the tyrosine kinase activity of epidermal growth factor receptor in trophoblasts. Our observations elucidate a ligand-dependent selective cross-communication between GnRH receptor and epidermal growth factor receptor signaling systems in human trophoblastic cell, and this would further our understanding on the differentially biological significance of these two forms of GnRH in extrapituitary tissues.
