摘要
一、目的
胚胎植入是十分复杂的过程，需要子宫内膜与胚胎在时间和空间上的同步协调。一方面，胚胎发育至胚泡阶段；另一方面，子宫内膜发育到允许胚胎侵入的接受态。在着床窗口期，子宫内膜经历一系列的形态学和生化改变，有利于胚胎植入。细胞表面糖蛋白介导细胞与细胞之间，细胞与细胞外基质之间的黏附。CD82糖蛋白属于跨膜四糖蛋白，可以抑制细胞的转移和迁移。研究表明：人类母胎界面的蜕膜细胞大量表达CD82蛋白，提示CD82可能参与胚胎植入。
子宫内膜的周期性变化受到卵巢激素的调控。在这些激素中，孕激素对于人类妊娠的的建立和维持起到决定性的作用。同时，接受态的子宫内膜与胚胎之间的黏附也受到孕激素的调控。孕激素受体是很多避孕药的靶位点。米非司酮(RU486)是一种孕激素受体的拮抗剂，被认为是一种常用的避孕药物。RU486的避孕机制甚多，但是其与着床窗口期的标志性分子岩藻糖基转移酶IV (FUT4)之间的关系尚无报道。
子宫内膜从非接受态向接受态转变的过程中，许多特异性的分子及其在子宫内膜表面的受体或者配体出现时空特异性的表达，有利于胚胎着床。S100A10及其配体Annexin A2形成异四聚体移位到细胞膜上，发挥多种生物学作用。研究发现，S100A10在早期妊娠的小鼠及恒河猴的植入位点显著上调。而Annexin A2蛋白在妊娠期的母胎界面持续增高。提示我们S100A10/Annexin A2可能参与胚胎植入。
本文通过对CD82，S100A10以及Annexin A2四个着床相关分子在人类月经周期不同阶段的表达和调控的研究，进一步探讨它们在生殖过程中的功能和作用机制，为阐明它们在生殖中的作用提供理论依据。同时，对生殖疾病的治疗以及辅助生殖中妊娠成功率的提高具有一定的意义。
二、方法
1.采用免疫组织化学检测CD82，S100A10，Annexin A2蛋白的表达及定位。
2.利用脂质体转染法将重组的CD82过表达质粒或CD82干扰质粒(CD82-siRNA)转染至人子宫内膜细胞系(RL95-2/HEC-1A)中。其中，RL95-2细胞系和HEC-1A细胞系分别代表高/低接受态的子宫内膜上皮细胞。
3.采用RT-PCR方法检测CD82，FUT4基因表达。
4.采用real-time PCR方法检测S100A10，Annexin A2基因表达。
5.采用Western blot检测CD82，FUT4，S100A10，Annexin A2蛋白表达。
6.采用间接免疫荧光方法检测CD82的表达。
7.利用黏附实验观察和分析胚胎细胞与子宫内膜细胞之间的黏附情况。
三、结果
（一）CD82在月经周期及不同接受态子宫内膜细胞中的差异性表达分析
1.通过免疫组化方法检测到CD82在着床窗口期的人类子宫内膜中的表达出现峰值。
2.应用RT-PCR、Western blot和间接免疫荧光方法检测到RL95-2细胞CD82的表达高于HEC-1A细胞。
3.应用RT-PCR和Western blot发现孕激素可以刺激CD82在RL95-2细胞和HEC-1A细胞中的表达。
4. CD82干扰质粒抑制胚胎细胞与RL95-2细胞的黏附率；CD82过表达质粒促进胚胎细胞与HEC-1A细胞的黏附率；CD82抗体封闭RL95-2或者HEC-1A细胞，可抑制胚胎细胞与子宫内膜细胞的黏附率。
5. CD82干扰质粒可以抑制RL95-2细胞中FAK信号通路的激活，CD82过表达质粒可以激活HEC-1A细胞中FAK信号通路。
（二）米非司酮(RU486)通过调节CD82抑制岩藻糖基转移酶IV的表达抑制胚胎体外黏附
1. RU486抑制JAR细胞与RL95-2单层之间的黏附。
2.采用RT-PCR筛选RL95-2细胞中的FUT家族基因，发现RU486对于FUT4基因表达的抑制最为明显。
3.应用RT-PCR和Western blot检测到RU486抑制RL95-2细胞以及流产妇女子宫内膜中FUT4的表达。
4. RU486抑制RL95-2细胞中CD82的基因以及蛋白表达。
5. CD82干扰质粒抑制RL95-2细胞中FUT4的表达，CD82过表达质粒促进RL95-2细胞中FUT4的表达。
6. RU486通过RU486/CD82/FUT4信号通路抑制胚胎与子宫内膜细胞的黏附。
（三）S100A10及其配体Annexin A2在人类月经周期子宫内膜中的表达变化
1.通过免疫组化和Western blot检测到S100A10和Annexin A2蛋白均在着床窗口期的人类子宫内膜中出现表达峰值。主要定位于腔上皮和腺上皮的胞浆、胞膜上。
2.应用real-time PCR检测到S100A10和Annexin A2的mRNA均在着床窗口期的人类子宫内膜中出现表达峰值。
四、结论
（一）CD82在月经周期及不同接受态子宫内膜细胞中的差异性表达分析
1.CD82在着床窗口期的人类子宫内膜中的表达呈现峰值。同时，CD82在高接受态的子宫内膜细胞系RL95-2中表达高于其在低接受态子宫内膜细胞系HEC-1A中。提示CD82可以作为子宫内膜接受态的标志物。
2.孕激素可以刺激CD82的表达。上调或抑制细胞中CD82表达，可以影响胚胎与子宫内膜的黏附率。说明CD82在胚胎植入的过程中发挥作用。
3.CD82通过调节RL95-2以及HEC-1A细胞中FAK信号通路的激活，参与胚胎植入。
（二）米非司酮(RU486)通过调节CD82抑制岩藻糖基转移酶IV的表达抑制胚胎体外黏附
1. RU486能够明显抑制RL95-2细胞中FUT4的表达。而且，服用RU486流产妇女的子宫内膜中FUT4的表达较物理性流产的妇女更低。表明FUT4受孕激素受体的调控，从而在胚胎植入过程中发挥作用。
2.上调或抑制RL95-2细胞中CD82的表达，可以调节RL95-2细胞中FUT4的合成水平，进而影响胚胎与子宫内膜的黏附率。结果表明CD82介导FUT4在胚胎植入过程中的作用。
3. RU486抑制CD82的表达，RU486通过RU486/CD82/FUT4信号通路抑制胚胎与子宫内膜的黏附。
（三）S100A10及其配体Annexin A2在人类月经周期子宫内膜中的表达变化
1. S100A10蛋白及mRNA在增生期和分泌期的子宫内膜中持续表达，分泌期的表达明显高于增生期。其表达峰出现在着床窗口期。说明CD82在胚胎植入的过程中发挥作用，可以作为子宫内膜接受态的标志物。
2. Annexin A2蛋白及mRNA在增生期不表达，在分泌中晚期的表达较高，与着床窗口期相一致。提示AnnexinA2可能是子宫内膜接受态的建立所必须的，可以成为评价内膜接受性的标志物。
I. Objective
Embryo implantation is a process that requires both temporal and spatialsynchronisation of the uterine endometrium and the embryo. A series of molecules inthe endometrium change dynamically in menstrual cycles. Especially during thewindow of implantation, expression of some molecules facilitates the process of embryoimplantation. Glycoproteins, found on cell surfaces, are involved the adhesion of cellsto other cells, and adhesion of cells to the extracellular matrix. CD82is a glycoproteinthat belongs to the transmembrane4superfamily and it can inhibit metastasis. Decidualcells at the maternal-fetal interface express a significant amount of CD82, indicating thatCD82may participate in embryo implantation.
The endometrial cycle is regulated by estrogen and progesterone. Indeed,progesterone plays critical roles for the embryo implantation and is required for themaintenance of pregnancy. In humans, the receptivity of endometrium for embryoadhesion is regulated closely by progesterone. Progesterone and the progesteronereceptor are the targets of many contraceptive drugs. Mifepristone (RU486) is acommon contraceptive drug that acts as a competitive progesterone receptor antagonist.There are many contraceptive mechanisms of RU486, but the relationship betweenRU486and fucosyltransferase IV which is a marker of endometrial receptivity has notbeen reported.
The S100A10is also called Annexin A2ligand. S100A10/Annexin A2tetramertransfers into cell membranes and is involved in many biological functions. It has beenreported that S100A10is highly expressed at implantation sites in mice and rhesus monkeys of early pregnancy. Annexin A2increases progressively during gestation inhuman fetomaternal interface.
In this study, we research the expression and regulation of CD82, S100A10andAnnexin A2on cell surface, and evaluate their roles on cell surface during implantation.The study will promte the further elucidation of the mechanism in embryo implantaion.
II. Methods
1. Expression and localization of CD82, S100A10and Annexin A2in the humanendometrium were analysed by immunohistochemistry.
2. The recombinant vector was transfected into cells.
3. The expression of CD82and FUT4were detected by the methods of RT-PCR.
4. The expression of S100A10and Annexin A2were detected by the methods ofreal-time PCR.
5. The expression of CD82, FUT4, S100A10and Annexin A2were detected bythe method of Western blot
6. Indirect immunofluorescence staining was used to detect CD82protein.
7. Detect the percent adhesion of JAR cell adhesion to RL95-2or HEC-1A cellmonolayer.
III. Results
(I) CD82expression alters with human endometrial cycles and affects the uterineendometrial receptivity in vitro
1. Immunohistochemistry found that the highest expression of CD82occurred inmid-and late-secretory phases which are considered the window of implantation.
2. The expression of CD82on RL95-2cells was also higher than on HEC-1A cellsby RT-PCR, Western blot and indirect immunofluorescence staining.
3. Progesterone induced the expression of CD82in both RL95-2and HEC-1Acells by RT-PCR and Western blot
4. RT-PCR, Western blot and indirect immunofluorescence staining found that theexpression of CD82was dramatically decreased by CD82-siRNA transfection incomparison to untransfected controls. The percent adhesion of JAR cells to RL95-2cellmonolayer was inhibited by CD82-siRNA or CD82antibody. Inversely, the percentadhesion of JAR cells to HEC-1A cell monolayer was promoted by CD82expressionplasmid.
5. To study the effect of CD82expression on FAK signaling pathway, tyrosinephosphorylation of FAK and pTYr was assessed by Western blot. In RL95-2cells, CD82knocking down cells expressed less pFAK and pTYr. Meanwhile, overexpressionof CD82in HEC-1A cells could increase the synthesis of pFAK and pTYr.
(II) Mifepristone(RU486) decreases the expression of fucosyltransferase
IV mediated by CD82and inhibits the adhesion of embryos in vitro
1. RU486inhibited the adhesion of JAR cells to RL95-2monolayer
2. RT-PCR detected the inhibition of RU486on the expression profile of variousFUTs in RL95-2cells. RU486predominantly decreased FUT4mRNA expression.
3. RU486inhibited the expression of FUT4in RL95-2cells and in humanendometrial tissues by RT-PCR and Western blot.
4. RU486inhibited the expression of CD82in RL95-2cells by RT-PCR andWestern blot.
5. CD82-siRNA inhibited the expression of FUT4in RL95-2cells. Meanwhile,overexpression of CD82increased the expression of FUT4in RL95-2cells.
6. Inhibition of embryonic adhesion by RU486correlated with RU486/CD82/FUT4signaling pathway.
(III) Cyclic changes of S100A10and Annexin A2expression in humanendometrium
1. Immunohistochemistry and Western blot found that the highest expression ofS100A10and Annexin A2protein occurred in mid-secretory phases in the cytoplasmand cytomembrane of the luminal and glandular epithelia, scatteredly and weakly instromal cells.
2. Relative mRNA quantity of S100A10and Annexin A2was analyzed byreal-time PCR. S100A10and Annexin A2mRNA was significantly up-regulated duringmid-secretory phases of the menstrual cycle compared with other stages.
IV. Conclusions
(I) CD82expression alters with human endometrial cycles and affects the uterineendometrial receptivity in vitro
1. The highest expression of CD82occurred in the window of implantation.Meanwhile, the expression CD82on RL95-2cells is higher than which on HEC-1Acells. The results indicate that CD82may been considered as an endometrial receptivitymarker.
2. Progesterone facilitates embryo implantation by up-regulating CD82-dependentembryo-endometrial adhesion. Therefore, CD82plays a role in embryo implantation.
3. CD82can regulate the FAK signaling pathway in RL95-2and HEC-1A cells and participates embryo implantation.
(II)Mifepristone(RU486) decreases the expression of fucosyltransferase IVmediated by CD82and inhibits the adhesion of embryos in vitro
1. FUT4is regulated by progesterone recepter and participates embryoimplantation.
2. CD82facilitates embryo implantation by up-regulating FUT4-dependentembryo-endometrial adhesion.
3. RU486inhibits embryonic adhesion through an RU486/CD82/FUT4pathway.
(III) Cyclic changes of S100A10and Annexin A2expression in humanendometrium
1. The highest expression of S100A10occurred in the window of implantation.The results indicate that S100A10may been considered as an endometrial receptivitymarker.
2. Annexin A2is necessary for establishment of endometrial receptivity and maybeen considered as a marker.
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