G蛋白耦联受体30与激素依赖性肿瘤

雌激素是类固醇激素家族中的一员,是人体中一种重要的激素,调节多种组织与器官的生理与病理效应。传统认为雌激素像其他类固醇激素一样是一个核转录因子,通过“核转录效应”发挥作用,然而该作用机制并没有使激素依赖性肿瘤得到有效的控制。近年来研究表明雌激素还具有生长因子样的“非核效应”,该过程仅需要数秒钟至数十分钟,因此又称“快速效应”。研究表明,G蛋白耦联受体30（GPR30）介导了雌激素的“非核效应”。GPR30与雌激素结合后可快速活化细胞内第二信使信号,诱导细胞外信号调节激酶（ERK）活化、磷脂酰肌醇3激酶（P13K）活化、钙动员及环磷酸腺苷（cAMP）生成等,参与雌激素非核效应的调节及雌激素依赖性肿瘤的发生和发展。     

G蛋白耦联雌激素受体-1与卵巢癌

G蛋白耦联雌激素受体-1(G protein-coupled estrogen receptor l,GPER-1)是一种新型的雌激素受体,能够介导雌激素的快速非基因组效应.GPER-1与雌激素具有高亲和力,能与天然雌激素和人工合成雌激素结合,快速激活细胞内第二信使或级联信号通路,间接调节转录活动,从而介导雌激素的生物学效应.GPER-1的亚细胞定位存在争议,因其亚细胞定位可能取决于不同的细胞类型.另外,性别、年龄等内在因素以及细胞外刺激、损伤等外在因素也影响GPER-1在质膜的相对丰度.近年来研究表明GPER-1的表达与女性生殖系统肿瘤的发生、发展密切相关,在卵巢癌组织中高表达,参与卵巢癌的发生发展,并可能作为评价卵巢癌患者预后的指标,有望成为卵巢癌重要的治疗靶点.     

丝裂原活化蛋白激酶信号转导通路与子宫内膜癌

丝裂原活化蛋白激酶(MAPK)通路目前已鉴定出4条[细胞外信号调节激酶(ERK)1/2、P38丝裂原活化蛋白激酶(P38)、c.Jun氨基未端激酶(JNK)和ERK5],其中ERK1/2通路可被多种刺激活化,通过调控细胞周期,抑制细胞凋亡,促进细胞增殖、迁移和侵袭等而与肿瘤的发生发展密切相关.许多子宫内膜痛相关因素通过MAPK/ERK通路起作用.雌激素可以通过非基冈组转录效应迅速激活MAPK通路促进子宫内膜的的发生发展.综述MAPK/ERK信号通路的研究进展,重点论述MAPK/ERK信号通路与子宫内膜癌的关系及分子机制,以及MAPK/ERK通路抑制剂在肿瘤防治方面的临床应用前景.     

雌激素膜性受体GPR30/GPER的研究现状

雌激素对女性生理变化或病理改变都起到重大的作用。传统理论认为,雌激素通过经典受体ERα/β调控转录反应或介导细胞信号转导。G蛋白耦联受体30（GPR30）,又称G蛋白耦联雌激素受体（GPER）,是一种新型的雌激素受体,能与雌激素或其衍生物、拮抗剂特异性结合并发挥生物学效应。近期发现在恶性肿瘤,如乳腺癌、子宫内膜癌、卵巢癌中有GPR30过表达。研究GPR30与恶性肿瘤发生发展的关系,以期在雌激素相关疾病尤其是肿瘤中寻找新的治疗靶点。     

雌激素膜性受体GPR30/GPER的研究现状

雌激素对女性生理变化或病理改变都起到重大的作用。传统理论认为,雌激素通过经典受体ERα/β调控转录反应或介导细胞信号转导。G蛋白耦联受体30（GPR30）,又称G蛋白耦联雌激素受体（GPER）,是一种新型的雌激素受体,能与雌激素或其衍生物、拮抗剂特异性结合并发挥生物学效应。近期发现在恶性肿瘤,如乳腺癌、子宫内膜癌、卵巢癌中有GPR30过表达。研究GPR30与恶性肿瘤发生发展的关系,以期在雌激素相关疾病尤其是肿瘤中寻找新的治疗靶点。     

丝裂原活化蛋白激酶通路与雌激素受体信号调控

丝裂原活化蛋白激酶(MAPK)信号转导通路是一组可以被多种细胞外信号激活的丝/苏氨酸激酶,参与细胞的多种生物学行为.雌激素为一种细胞外信号,可以通过雌激素受体(ER)的基因组作用和非基冈组作用对细胞功能起调节作用.MAPK信号通路信号转导与ER调控关系密切,其既可以通过ER经典的基因组效应介导多种细胞广泛的生理效应,又可以通过ER非基因组效应实现快速信号通路转导.调控基因转录、细胞的增殖.受体与信号通路之间调控的最终生物学效应可表现在心血管系统、神经系统和恶性肿瘤等诸多方面,就MAPK信号转导通路与ER调控的分子机制及其生物学效应综述.     

新型雌激素受体GPR30与雌激素非基因组效应的研究进展

雌激素不仅在生殖系统,而且在多个系统中发挥着广泛且重要的作用。近来许多研究证实,除了传统的介导基因组信号通路的雌激素受体(ER)-ERα和ERβ外,还存在着新型的调节非基因组信号的ER-G蛋白偶联受体30(GPR30),它能够参与多种细胞的众多生理病理过程。尽管它们有时存在交叉作用,但GPR30的功能与经典受体明显不同,它在雌激素相关疾病发病机制中的作用逐渐成为国内外学者研究的热点。     

雌激素及其受体对T淋巴细胞免疫功能的调节

雌激素和核内雌激素受体(ER)或膜相关雌激素受体结合,分别通过基因途径和快速信号反应途径调节T淋巴细胞功能.雌激素和雌激素受体从多个方面调节T淋巴细胞的免疫功能:雌激素能调节辅助性T细胞1(Th1)和辅助性T细胞2(Th2)的比例,使其向Th2型细胞偏移;雌激素也能影响CD4+/CD8+T细胞的比例;雌激素和ER影响T细胞的分化和成熟.     

丝裂原活化蛋白激酶信号转导通路与子宫内膜癌

丝裂原活化蛋白激酶（MAPK）通路目前已鉴定出4条[细胞外信号调节激酶（ERK）1,2、P38丝裂原活化蛋白激酶（P38）、c-Jun氨基末端激酶（JNK）和ERK5],其中ERK1／2通路可被多种刺激活化,通过调控细胞周期,抑制细胞凋亡。促进细胞增殖、迁移和侵袭等而与肿瘤的发生发展密切相关。许多子宫内膜癌相关因素通过MAPK／ERK通路起作用。雌激素可以通过非基因组转录效应迅速激活MAPK通路促进子宫内膜的的发生发展。综述MAPK／ERK信号通路的研究进展,重点论述MAPK／ERK信号通路与子宫内膜癌的关系及分子机制,以及MAPK／ERK通路抑制剂在肿瘤防治方面的临床应用前景。     

丝裂原活化蛋白激酶通路与雌激素受体信号调控

丝裂原活化蛋白激酶（MAPK）信号转导通路是一组可以被多种细胞外信号激活的丝／苏氨酸激酶,参与细胞的多种生物学行为。雌激素为一种细胞外信号,可以通过雌激素受体（ER）的基因组作用和非基因组作用对细胞功能起调节作用。MAPK信号通路信号转导与ER调控关系密切．其既可以通过ER经典的基因组效应介导多种细胞广泛的生理效应．又可以通过ER非基因组效应实现快速信号通路转导,调控基因转录、细胞的增殖。受体与信号通路之间调控的最终生物学效应可表现在心血管系统、神经系统和恶性肿瘤等诸多方面,就MAPK信号转导通路与ER调控的分子机制及其生物学效应综述。     

Induction of estrogen receptor-α and -β activities by synthetic progestins

The cellular action of steroid hormones is mediated by specific receptors. Recently, two different estrogen receptors (ER), α and β, have been cloned with a specific tissue distribution. Active estrogen as well as active progestin are compounds of oral hormonal contraceptives and hormone replacement therapy.

To examinate the regulation of ER-α and -β activities after treatment with synthetic progestins and synthetic and natural estrogens, COS 7 cells were transfected with the vector expressing ER-α and -β in combination with a luciferase reporter vector. ER-α activity was upregulated in the presence of synthetic progestins in a dose-dependent manner. Norethisterone, norethynodrel and desogestrel proved to be the most potent stimulatory agents of ER-α expression. On the other hand, not all progestins exhibited a stimulatory action on ER-β activity. Only norgestrel, levonorgestrel, norethynodrel and norethisterone induced ER-β-activating functions in a dose-dependent manner. Luciferase activity due to estrogen stimulation served as a positive control.

Our results indicate that progestins have different effects on the activities of ER-α and -β.     

Prognostic significance of the estrogen receptor beta (ERβ) isoforms ERβ1, ERβ2, and ERβ5 in advanced serous ovarian cancer

Objective

In the present study we have examined the pattern of expression of the full length estrogen receptor β (ERβ1) and two ERβ splice variant isoforms (ERβ2, ERβ5) in well-characterized advanced serous ovarian cancers.

Methods

Immunohistochemistry was performed with ERβ1, ERβ2, and ERβ5 antibodies and results were correlated with pathological and clinical follow-up data. Expression of ERβ isoforms in a panel of ovarian cancer cell lines and human tumor xenografts was also assessed.

Results

Immunohistochemical staining revealed cellular compartment-specific distribution for each isoform in malignant ovarian tissues exhibiting both nuclear staining and cytoplasmic staining. Patients with cytoplasmic ERβ2 expression had significantly worse outcome (p = 0.006 at the multivariate analysis), the 5-year survival rate being nearly 28% for patients who did express cytoplasmic ERβ2, and 60% in negative patients. Cytoplasmic ERβ2 expression was also found to be significantly associated with chemoresistance. In concordance with clinical results both nuclear and cytoplasmic expressions were observed for the three isoforms in the cancer cell lines and human tumor xenografts tested.

Conclusions

This is the first study to uncover an unfavorable prognostic role of ERβ2 in advanced serous ovarian cancer. If anomalies of ERβ2 cytoplasmic expression could be demonstrated to represent an independent unfavorable prognostic marker and/or a marker predicting chemoresistance in advanced serous ovarian cancer, its immunohistochemical assessment at the time of surgery, could help to recognize candidates for clinical trials of new interventions.     

Estrogen replacement therapy: An overview

Levels of circulating estrogen fall during the perimenopausal period, resulting in changes in the postmenopausal woman's genitourinary tract, central nervous and cardiovascular systems, skin, and bone. Exogenous estrogen minimizes the benign symptoms and prevents the increased incidence of osteoporosis and atherosclerotic heart disease that accompany estrogen deficiency. Thus to avoid the recognized problems of estrogen deficiency, nearly all women should begin a lifelong course of estrogen replacement therapy during the perimenopausal period.     

Estrogen levels and estrogen receptors in patients with stress urinary incontinence and pelvic organ prolapse.

OBJECTIVES: To investigate the histologic characteristics of tissues presumed to be the cause of urinary stress incontinence and pelvic organ prolapse. METHODS: Cardinal ligament and uterosacral ligament samples were obtained from 73 women undergoing hysterectomy. The evaluation of estrogen receptors (ERs) by immunohistochemical staining was semi-quantitative. Serum estrogen was determined by ELISA. Statistical analyses were performed by the independent-sample t-test and one-way ANOVA. RESULTS: Serum estradiol levels and ER values in the premenopausal women with pelvic organ prolapse were significantly lower than in the control group (P<0.01). A positive correlation was found between ERs and the number of postmenopausal years (P<0.01). ER values were similar in the cardinal and uterosacral ligaments. CONCLUSIONS: Serum estrogen levels and ER values are significantly lower in the uterine ligaments of premenopausal women with pelvic organ prolapse, and there was a positive correlation between ER values in the uterine ligaments and the duration of postmenopausal years. Serum estrogen levels and ER values were similar in the cardinal ligament and the uterosacral ligament.     

Immunohistochemical study of distribution of estrogen receptors in corpus and cervix uteri

Summary An immunohistochemical assay based on monoclonal antiestrophilin antibodies has been used to localize estrogen receptor (ER) in frozen sections of normal human endometrial, myometrial and cervical tissues from menstruating, hormonally treated, pregnant and postmenopausal women. Specific staining was confined to the cellular nuclei. In proliferative phase endometrium, postmenopausal emdometrium, and endometrium from patients treated with hormone ERs were easily detected in most glandular and stromal cells. After ovulation and in early pregnancy a quick and distinct decrease of ER expression was noted. This was especially the case with the more superficial layers of endometrium (endometrium functionals), the majority of whose cells had either weak localization of ER or none at all. In the endometrium basalis, however, the reduction of ER localization turned out to be more moderate. More then half of the epithelial and stromal cells displayed nuclear staining, partly strong. The myometrium of the corpus uteri showed a similar ER localization and dependence on hormonal stage when compared with the endometrium functionalis. The endocervical mucosa displayed a high degree of ER expression in the proliferative phase in postmenopausal women and in women who had been treated with hormones. Unlike the endometrium and myometrium, the endocervical glands underwent minimal changes in nuclear ER content during the menstrual cycle. Although the endocervical stroma showed cyclic alterations in ER levels, their reduction after ovulation was less marked than in the corresponding endometria. In cervical squamous epithelium ER localization was predominantly confined to the basal layers. In the course of cellular maturation, specific nuclear staining vanished. In the proliferative phase, after the menopause and in early pregnancy, the basal, parabasal and intermediate cells were specifically stained. In the postovulatory phase. However, nuclear staining was confined to the basal and parabasal cells. Hormonally treated squamous epithelia almost completely lacked nuclear ER localization.Dedicated to Professor V. Becker, Erlangen, on the occasion of his 65th anniversary     

Biosynthesis and physiologic effects of estrogen and pathophysiologic effects of estrogen deficiency: A review

Women are increasingly spending more years of their lives beyond the menopause, which places them at risk for various health problems due to estrogen deficiency. Tissues and organs with estrogen receptors such as the ovaries, endometrium, vaginal epithelium, hypothalmus, urinary tract, and skin are directly affected by a lack of estrogen production. Other tissues in which estrogen receptors have not been consistently identified, such as bone, are also affected by waning levels of estrogen. The postmenopausal woman frequently experiences neuroendocrine changes (hot flashes) that often dissipate over time and a steady rise in her risk of cardiovascular disease, which approaches that in men of comparable age.     

中药复方“更年健”对雌性大鼠老化过程中脾细胞雌激素受体的影响

根据中药复方“更年健”对更年期综合征疗效及神经内分泌免疫调节的作用，本文采用放射配体结合分析法（羟基磷灰石吸附分离）－ＨＡＰ法观察“更年健”对雌性大鼠老化过程中脾细胞雌激素受体的影响，并和用雌激素组对比，结果表明１２月龄以后脾细胞ＥＲ水平明显下降，灌服“更年健”后各月龄点脾细胞ＥＲ水平又明显上升，而此水平在雌激素组则明显下降，提示“更年健”对免疫细胞ＥＲ有明显上调作用。     

雌激素受体及其变异体与子宫内膜癌的关系

经典雌激素受体（ER）及其变异体、雌激素膜受体（mER）参与介导雌激素不同生物效应。多项研究表明,雌激素与子宫内膜癌的发生、发展过程密切相关,目前普遍接受的子宫内膜癌形成的原因是子宫内膜受到过度雌激素刺激并缺乏孕激素拮抗。雌激素发挥其效应主要依赖ER,研究ER对了解子宫内膜癌发生、发展的可能机制起到了重要作用,并为子宫内膜癌的诊断及治疗提供了新的思路。综述ER及其变异体的结构、功能及其与子宫内膜癌的关系,为深入研究提供思路。