GPR30阳性表达对子宫内膜癌患者预后的影响及其与雌、孕激素受体表达的相关性

目的 分析新型雌激素受体GPR30表达对子宫内膜癌患者预后的影响并探讨其与雌、孕激素表达的关系。方法 收集该院妇产科经病理确诊为子宫内膜癌的石蜡切片,采用免疫组化法检测GPR30、雌激素受体、孕激素受体表达,并分析其对子宫内膜癌的临床意义和分析三者间的关系。结果 GPR30阳性表达率与子宫内膜癌的FIGO分期、组织分级以及肌层浸润深度有关联(P＜0.05),与淋巴结转移无明显相关性(P＞0.05)。GPR30表达阳性率在子宫内膜癌中表达显著高于增殖期子宫内膜(P＜0.05),PR表达阳性率在子宫内膜癌与增殖期子宫内膜差异显著(P＜0.05),ER表达阳性率在两者间无差异(P＞0.05)。子宫内膜癌GPR30与ER阳性共表达率为61.2%(30/49),呈正相关(r=0.315,P=0.021);与 PR阳性共表达率为57.1%(28/49),呈正相关(r=0.303,P=0.027)。结论 GPR30阳性表达对子宫内膜癌的病理分期、组织分级以及肌层浸润深度相关,对子宫内膜癌预后产生重要作用;GPR30与ER、PR间存在共表达的交谈或调节作用。     

雌性激素受体甲基化与中枢神经系统疾病的研究进展

DNA甲基化作为一种主要的表观遗传修饰模式，与许多疾病的发生及发展相关。近年来研究发现，雌激素对中枢神经系统具有保护作用。雌激素的作用通过雌激素受体发挥。雌激素受体在中枢及外周均有分布，而雌激素受体甲基化异常会影响表达，并会引起缺血性脑卒中、阿尔茨海默病、帕金森病等多种中枢神经系统疾病。该文总结了近年来关于体内雌激素受体甲基化过程以及对中枢神经系统相关疾病的研究进展。     

玉米赤酶烯酮对大鼠子宫雌激素受体影响的探讨

目的探讨玉米赤霉烯酮对子宫雌激素受体的影响及其雌激素样作用机制。方法 30只大鼠行双侧去卵巢手术后随机分为阴性对照组（蒸馏水）、低,中、高剂量玉米赤霉烯酮组（0.01mg/kg、0.05mg/kg、0.20mg/kg）和阳性对照组（0.08mkg雌二醇）,连续用药3d后取子宫,采用放射性配基结合分析法和雌激素受体结合试验检测雌激素受体数量。结果玉米赤霉烯酮各浓度组放射活性与阴性对照组比较,差异有统计学意义（P≤0.05）。玉米赤霉烯酮各浓度组雌激素受体数量与阴性对照组比较,差异无统计学意义（P≥0.05）。结论玉米赤霉烯酮可能是通过影响雌二醇与雌激素受体结合和雌激素受体的数量显示雌激素样作用。     

雌激素及其受体信号转导途径的研究进展

雌激素因具有广泛的生物学效应，日益成为研究的热点。雌激素的作用是由雌激素受体（ER）介导的，ER具有广泛的组织分布，包括生殖系统、骨骼、心血管系统等，为雌激素发挥生物学效应提供了保证。本文就雌激素及其受体信号转导途径的相关国内外研究进展作一综述。     

烟酸受体GPR109a及相关激动剂的研究进展

烟酸是临床应用几十年的降血脂药物,近年来研究发现,烟酸作用于G蛋白偶联受体109a（GPR109a）和GPR109b,该受体主要在脂肪细胞和多种免疫细胞中表达。烟酸受体的发现以及对相关不良反应作用机制的研究为寻找活性更强、不良反应较小的降脂药物开启了一条新的途径,为相关心血管疾病及糖尿病并发症的治疗提供了新的思路。本文对以GPR109a为靶标的药物研究成果进行综述。     

GPR120和GPR40表达与卵巢癌临床病理特征及预后的关系

目的 探讨G蛋白偶联受体(GPR)120与GPR40在卵巢癌中的表达及其作为预后分子标志物的临床价值。方法 通过免疫组织化学染色检测128例卵巢癌患者的石蜡包埋样本中GPR120与GPR40表达。分析GPR120、GPR40表达与卵巢癌临床病理特征之间的关系，采用Kaplan-Meier法绘制高表达和低表达GPR120、GPR40患者的生存曲线，Cox风险回归模型分析卵巢癌患者无病生存(DFS)率的影响因素。结果 卵巢癌患者GPR120与GPR40阳性表达率分别为62.5%(80/128)和56.3%(72/128)。FIGOⅡ—Ⅲ期和组织学G3级患者的GPR120和GPR40高表达率分别高于FIGOⅠ期与组织学G1—G2级。生存分析表明，GPR120高表达者的4年DFS较低表达者下降(56.9%vs. 70.7%,Log-rankχ²=5.144,P=0.023)。此外，GPR40高表达者的DFS率亦低于低表达组(57.7%vs. 68.4%,Log-rankχ²=4.491,P=0.034)。单、多变量Cox回归分析认定GPR120高表达...     

GPR30在全氟辛烷磺酰基化合物诱导GC-1细胞凋亡中的作用

目的研究全氟辛烷磺酰基化合物(perfluorooctane sulfonate,PFOS)对生精细胞凋亡的影响,并探讨其可能机制及G蛋白偶联受体30(G protein-coupled receptor 30,GPR30)在此过程中的作用。方法以GC-1小鼠精原细胞株为染毒模型,设置对照组和PFOS染毒组(50、100和200μmol/L)。运用MTT法检测GC-1细胞的存活率;Annexin VFITC/PI双染色法检测GC-1细胞凋亡;采用蛋白质印迹技术(Western blot)检测不同剂量PFOS及同时加入GPR30特异性阻断剂G15后对生精细胞凋亡相关蛋白表达的影响。结果 PFOS能够显著抑制GC-1细胞的增殖、促进GC-1细胞凋亡;PFOS染毒后,GC-1细胞中GPR30及凋亡相关蛋白Cleaved caspase-3、Bax表达显著升高;G15阻断GPR30的表达后,PFOS对Cleaved caspase-3表达水平的提升作用被部分逆转。结论 PFOS能显著促进生精细胞凋亡,其机制可能是通过上调GPR30的表达继而激活线粒体凋亡通路,并最终影响精子发生。     

G蛋白偶联受体119激动剂的研究进展

G蛋白偶联受体119(GPR119)是近年来发现的治疗糖尿病药物的重要靶标。该受体激动后,既能升高血浆中GLP-1水平又能增加胰岛素的分泌,近年来受到世界多个制药公司的重视,开发了多个GPR119激动剂,部分已经进入临床研究。本文对GPR119激动剂近年来的研究进展做一综述。     

G蛋白偶联受体30在宫颈癌组织中的表达及临床意义

目的 分析G蛋白偶联受体30(GPR30)在宫颈癌组织中表达的临床意义.方法 选取2012年9月-2015年6月收集的68例宫颈病变组织标本,其中宫颈癌组38例,宫颈上皮内瘤样病变(CIN)组30例,另选择来院行妇科检查的20例正常宫颈组织作为对照组,观察3组宫颈组织CPR30的表达水平,并分析其与宫颈癌临床病理参数的关系.结果 宫颈癌组和CIN组宫颈组织GRP30表达阳性率和GRP30 mRNA相对表达量均高于对照组,且宫颈癌组高于CIN组(P＜0.05);不同分化程度、不同临床分期宫颈癌组织GPR30阳性率比较差异有统计学意义(P＜0.05).结论 GPR30参与宫颈癌的发生及进展,且与肿瘤分化程度、临床分期密切相关.     

去势雌性大鼠主动脉平滑肌细胞雌激素受体的变化

目的：探讨绝经后血管平滑肌细胞雌激素受体的变化。方法：采用切除双侧卵巢、高脂饲料喂养造模大鼠，观察去势雌性大鼠血脂的变化，并应用免疫组化法(SP法)测定主动脉平滑肌细胞雌激素受体变化。结果：去势雌性大鼠血脂代谢紊乱，主动脉平滑肌细胞雌激素受体水平下降。结论：绝经后女性心血管疾病发病率与雌激素受体水平下降有关。     

选择性雌激素受体调节剂的作用机制研究近况

选择性雌激素受体调节剂(SERM)在不同的靶组织可以表现为雌激素激动剂和(或)拮抗剂，本文综述了近年来关于SERM结构、ER亚型、共调节子、靶启动子、细胞亚型、细胞内信号通路、雌激素受体相关受体等对SERM组织选择性的影响的研究状况。     

雌激素受体与抑郁症的相关性研究进展

雌激素主要通过雌激素受体发挥抗抑郁作用。目前研究较多的是雌激素受体 α（ERα）、雌激素受体 β （ERβ）和 G蛋白偶联雌激素受体（GPER）。三者在雌激素的抗抑郁作用中发挥不同的效应,其中 GPER可能与雌激 素的快速抗抑郁作用有关。深入了解雌激素受体的不同效应对于寻找治疗抑郁症的新靶点,充分发挥雌激素的抗 抑郁作用,最大程度减少其不良反应具有重要意义。     

雌激素对卵巢切除后雌性大鼠心肌组织中雌激素受体表达的影响

目的：探讨雌激素对卵巢切除后雌性大鼠心肌组织中雌激素受体表达的影响。方法：雌性SD大鼠卵巢切除术（OVX）后1周,随机分成3组：OVX＋雌激素（0.15mg/kg,s.c.）、OVX＋生理盐水、对照组。4周后,Westernblotting检测α和β两种雌激素受体在心肌组织中的表达。结果：卵巢切除后,血清雌激素水平与对照组[（88±22vs403±59）pmol/L,P〈0.05]相比明显下降,左心室肌中两种雌激素受体表达均下降（P〈0.05）。给予雌激素后,血清雌激素水平上升为（3864±105）pmol/L,雌激素β受体表达增多（P〈0.05）,α受体表达下降（P〈0.05）。结论：雌激素改变卵巢切除后雌性大鼠心肌组织中雌激素受体的表达。     

Estrogen and pure antiestrogen fulvestrant (ICI 182 780) augment cell–matrigel adhesion of MCF-7 breast cancer cells through a novel G protein coupled estrogen receptor (GPR30)-to-calpain signaling axis

Fulvestrant (ICI 182 780, ICI) has been used in treating patients with hormone-sensitive breast cancer, yet initial or acquired resistance to endocrine therapies frequently arises and, in particular, cancer recurs as metastasis. We demonstrate here that both 17-beta-estradiol (E2) and ICI enhance cell adhesion to matrigel in MCF-7 breast cancer cells, with increased autolysis of calpain 1 (large subunit) and proteolysis of focal adhesion kinase (FAK), indicating calpain activation. Additionally, either E2 or ICI induced down-regulation of estrogen receptor α without affecting G protein coupled estrogen receptor 30 (GPR30) expression. Interestingly, GPR30 agonist G1 triggered calpain 1 autolysis but not calpain 2, whereas ER agonist diethylstilbestrol caused no apparent calpain autolysis. Furthermore, the actions of E2 and ICI on calpain and cell adhesion were tremendously suppressed by G15, or knockdown of GPR30. E2 and ICI also induced phosphorylation of extracellular regulated protein kinases 1 and 2 (ERK1/2), and suppression of ERK1/2 phosphorylation by U0126 profoundly impeded calpain activation triggered by estrogenic and antiestrogenic stimulations indicating implication of ERK1/2 in the GPR30-mediated action. Lastly, the E2- or ICI-induced cell adhesion was dramatically impaired by calpain-specific inhibitors, ALLN or calpeptin, suggesting requirement of calpain in the GPR30-associated action. These data show that enhanced cell adhesion by E2 and ICI occurs via a novel GPR30-ERK1/2-calpain pathway. Our results indicate that targeting the GPR30 signaling may be a potential strategy to reduce metastasis and improve the efficacy of antiestrogens in treatment of advanced breast cancer.     

Rapid activation of ERK1/2 and AKT in human breast cancer cells by cadmium

Cadmium (Cd), an endocrine disruptor, can induce a variety of signaling events including the activation of ERK1/2 and AKT. In this study, the involvement of estrogen receptors (ER) in these events was evaluated in three human breast cancer cell lines, MCF-7, MDA-MB-231, and SK-BR-3. The Cd-induced signal activation patterns in the three cell lines mimicked those exhibited in response to 17 beta-estradiol. Specifically, treatment of MCF-7 cells, that express ER alpha, ER beta and GPR30, to 0.5-10 microM Cd for only 2.5 min resulted in transient phosphorylation of ERK1/2. Cd also triggered a gradual increase and sustained activation of AKT during the 60 min treatment period. In SK-BR-3 cells, that express only GPR30, Cd also caused a transient activation of ERK1/2, but not of AKT. In contrast, in MDA-MB-231 cells, that express only ER beta, Cd was unable to cause rapid activation of either ERK1/2 or AKT. A transient phosphorylation of ER alpha was also observed within 2.5 min of Cd exposure in the MCF-7 cells. While the estrogen receptor antagonist, ICI 182,780, did not prevent the effect of Cd on these signals, specific siRNA against hER alpha significantly reduced Cd-induced activation of ERK1/2 and completely blocked the activation of AKT. It is concluded that Cd, like estradiol, can cause rapid activation of ERK1/2 and AKT and that these signaling events are mediated by possible interaction with membrane ER alpha and GPR30, but not ER beta.     

Antiestrogen, trans-tamoxifen modulation of human breast cancer cell growth

To gain further insight into how estrogens modulate cell function, the effects of estrogen on cell proliferation were studied in human breast cancer cells. We examined the effects of estrogen on the proliferation of three human breast cancer cell lines that differed in their estrogen receptor contents. Ten nM estradiol markedly stimulated the proliferation of MCF-7 human breast cancer cells that contained high levels of estrogen receptor (1.15±0.03 pmole/mg protein) over that of control. In T47D cells that contained low levels of estrogen receptor (0.23±0.05 pmole/mg protein), Ten nM estrogen slightly stimulated the proliferation over that of control. MDA-MB-231 cells, that contained no detectable levels of estrogen receptors, had their growth unaffected by estrogen. These results showed their sensitivity to growth stimulation by estrogen correlated well with their estrogen receptor content. Also we examined the effect of estrogen on cellular progesterone receptor level as well as plasminogen activator activity in MCF-7 cells. Ten nM estradiol showed maximal stimulation of progesterone receptor level as well as plasminogen activator activity in MCF-7 cells. It is not clear whether these stimulations of progesterone receptor and plasminogen activator activity by estrogen are related to the estrogen stimulation of cell proliferation of MCF-7 cells. Studies with estrogen in human breast cancer cells in culture indicate that sensitivity to growth stimulation by estrogen correlates well with estrogen receptor contents.     

选择性雌激素受体调节剂研究现状

乳腺癌已经成为危害女性健康的主要恶性肿瘤,选择性雌激素受体调节剂作为治疗乳腺癌的有效药物越来越受到人们的广泛关注。笔者对选择性雌激素受体调节剂的研究现状进行综述。     

The membrane estrogen receptor GPR30 mediates cadmium-induced proliferation of breast cancer cells

Cadmium (Cd) is a nonessential metal that is dispersed throughout the environment. It is an endocrine-disrupting element which mimics estrogen, binds to estrogen receptor alpha (ERα), and promotes cell proliferation in breast cancer cells. We have previously published that Cd promotes activation of the extracellular regulated kinases, erk-1 and -2 in both ER-positive and ER-negative human breast cancer cells, suggesting that this estrogen-like effect of Cd is not associated with the ER. Here, we have investigated whether the newly appreciated transmembrane estrogen receptor, G-protein coupled receptor 30 (GPR30), may be involved in Cd-induced cell proliferation. Towards this end, we compared the effects of Cd in ER-negative human SKBR3 breast cancer cells in which endogenous GPR30 signaling was selectively inhibited using a GPR30 interfering mutant. We found that Cd concentrations from 50 to 500 nM induced a proliferative response in control vector-transfected SKBR3 cells but not in SKBR3 cells stably expressing interfering mutant. Similarly, intracellular cAMP levels increased about 2.4-fold in the vector transfectants but not in cells in which GPR30 was inactivated within 2.5 min after treatment with 500 nM Cd. Furthermore, Cd treatment rapidly activated (within 2.5 min) raf-1, mitogen-activated protein kinase kinase, mek-1, extracellular signal regulated kinases, erk-1/2, ribosomal S6 kinase, rsk, and E-26 like protein kinase, elk, about 4-fold in vector transfectants. In contrast, the activation of these signaling molecules in SKBR3 cells expressing the GPR30 mutant was only about 1.4-fold. These results demonstrate that Cd-induced breast cancer cell proliferation occurs through GPR30-mediated activation in a manner that is similar to that achieved by estrogen in these cells.     

雌激素孕激素及受体在肝门部胆管癌中的表达

目的探讨雌、孕激素(ER、PR)及其受体在肝门部胆管癌的发生中的作用。方法应用放射免疫法测定42例肝门部胆管癌患者血中的雌、孕激素水平；应用免疫组织化学法，检测其组织中ER及PR表达水平。结果42例肝门部胆管癌患者中，雌、孕激素高于正常者分别占73．8％和69．0％，ER及PR阳性表达率分别为66．7％、和64．3％。与对照组相比，雌、孕激素水平及受体表达具有明显差异。结论肝门部胆管癌患者中，多数雌、孕激素水平高，ER及PR表达率高。雌、孕激素及受体可能在肝门部胆管癌发生和发展过程中起重要作用。     

胆囊病变组织中雌激素与孕激素受体表达和成石原因相关研究

目的 探讨胆囊病变组织雌激素受体（ER）与孕激素受体（PR）的表达及其在发病中的作用.方法 采用免疫组化法进行ER、PR的检测.结果 胆囊癌、胆囊炎伴胆石症患者的阳性表达率明显高于胆囊炎伴胆固醇沉着症、胆囊息肉及单纯性胆囊炎患者（P＜0.05）,ER及PR在胆囊癌及胆囊炎伴胆石症中的阳性表达率分别为100%、70%及100%、50%,其阳性表达率在胆囊炎伴胆石症、胆囊癌中呈现由少到多的关系.结论 雌激素通过诱导该受体表达增加了形成胆囊结石并进一步发展为胆囊癌的易感性.