促性腺激素釋放激素（gonadotropin-releasing hormone,GnRH）是由下丘腦合成的十肽激素,，主要功能是控制卵泡刺激素(FSH)和黃體生成素(LH)的釋放，在性別分化,、性腺發(fā)育以及生殖過程中起重要調(diào)節(jié)作用,。迄今為止，在人體內(nèi)發(fā)現(xiàn)存在GnRH-I和GnRH-II兩種亞型,。已有證據(jù)表明,，GnRH-I和GnRH-II除了在內(nèi)分泌系統(tǒng)中發(fā)揮核心作用外，還可直接作用于人胎盤的滋養(yǎng)層細(xì)胞,，促進(jìn)滋養(yǎng)層細(xì)胞侵潤母體子宮,，在胎盤發(fā)生、建立母胎循環(huán)的過程中發(fā)揮作用,。這兩種GnRH亞型在調(diào)節(jié)滋養(yǎng)層細(xì)胞侵潤行為時(shí)卻表現(xiàn)出不同的效應(yīng),，而關(guān)于二者發(fā)揮作用的信號(hào)通路以及不同效應(yīng)的分子機(jī)制尚不知曉。
中國科學(xué)院動(dòng)物研究所王雁玲研究員領(lǐng)導(dǎo)的研究組與加拿大英屬哥倫比亞大學(xué)Peter C.K. Leung教授的研究組合作,，利用原代培養(yǎng)的人滋養(yǎng)層細(xì)胞作為研究模型,，對(duì)GnRH-I和GnRH-II作用的分子機(jī)制進(jìn)行了深入研究。結(jié)果發(fā)現(xiàn),，GnRH-I和GnRH-II都能通過激活PKC,、ERK和JNK激酶調(diào)節(jié)滋養(yǎng)層細(xì)胞的侵潤，但是GnRH-II是通過轉(zhuǎn)導(dǎo)激活EGF受體酪氨酸激酶活性實(shí)現(xiàn)上述激酶的激活,，而GnRH-I的作用是EGF受體非依賴型的,。利用RNA干擾技術(shù)敲除I型GnRH受體，只有GnRH-I的促侵潤作用被阻斷,，而對(duì)GnRH-II的作用沒有顯著影響,，表明可能存在新的特異性的GnRH-II受體。該研究首次揭示了人胎盤中GnRH-I和GnRH-II通過不同的受體和信號(hào)交聯(lián)通路調(diào)節(jié)細(xì)胞侵潤行為,，而這種配體依賴性選擇信號(hào)通路的機(jī)制對(duì)于理解不同亞型GnRH在垂體外組織中的生理功能具有重要意義,。
以上研究成果最近發(fā)表于內(nèi)分泌學(xué)國際權(quán)威學(xué)術(shù)期刊 Molecular Endocrinology (Liu J, MacCalman CD, Wang YL, Leung PC. Molecular Endocrinology. 2009, 23(7):1014-1021)。第一作者劉璟為生殖病理研究組2007年畢業(yè)的博士研究生,，通訊作者王雁玲為生殖病理研究組組長,。這一工作受到國家重大科學(xué)研究計(jì)劃課題(No. 2006CB944008) 和中科院知識(shí)創(chuàng)新工程重要方向性項(xiàng)目(Grant No. KSCX2-YW-R-53)資助。（生物谷Bioon.com）
生物谷國慶專題：新中國生命科學(xué)60年
生物谷推薦原始出處：
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.
