子宫内膜癌雌,孕激素受体的定位检测

子宫内膜癌雌、孕激素受体的定位检测王艳琴，郭燕燕对子宫内膜癌雌激素受体（ＥＲ）及孕激素受体（ＰＲ）进行定位检测，可了解肿瘤的生物学行为，为临床估计预后，指导治疗提供更可靠的依据。一、资料与方法１．标本来源：选自１９９０年１０月至１９９３年３月我院、北...     

雌孕激素受体甲基化与子宫内膜癌研究进展

雌孕激素受体(ER,PR)的异常表达对于子宫内膜癌的治疗、预后显著相关.表观遗传学对于肿瘤的研究显示:DNA异常甲基化参与肿瘤发生、发展过程,最新研究显示ER,PR异常甲基化与子宫内膜癌发展、预后等密切相关.阐述两种受体甲基化在子宫内膜癌组织中的研究现状,针对存在问题,提出研究方向.     

雌、孕激素受体亚型及其在子宫内膜癌组织中的表达

雌激素受体（ER）存在α、β两种亚型，两者在结构上虽有相似之处，但功能却不尽相同，且在各组织中的表达方式及表达量不尽相同，孕激素受体（PR）也存在A、B两种亚型，对ERα和ERβ，PRA及PRB在正常子宫内膜组织，子宫内膜癌组织中的分布与及与子宫内膜癌分级的关系等方面进行简要综述。     

子宫内膜癌患者孕激素抵抗机制的研究

子宫内膜癌是发达国家最常见的妇科恶性肿瘤之一,也是女性癌症患者的第八大死亡因素,在我国其发病率仅次于宫颈癌。对早期、复发及有生育要求的子宫内膜癌患者,孕激素治疗是主要治疗措施。但部分子宫内膜癌患者对孕激素治疗不敏感(即孕激素抵抗),给临床治疗带来困难。研究发现,在机体循环过程中有多种因素可导致孕激素抵抗,其中孕激素受体的异常改变是目前孕激素抵抗的主要原因。此外,Fas/Fasl、PI3K/Akt、Survivin、EGFR及胰岛素抵抗等都与孕激素抵抗密切相关。     

雌孕激素受体甲基化与子宫内膜癌研究进展

雌孕激素受体（ER，PR）的异常表达对于子宫内膜癌的治疗、预后显著相关。表观遗传学对于肿瘤的研究显示：DNA异常甲基化参与肿瘤发生、发展过程，最新研究显示ER，PR异常甲基化与子宫内膜癌发展、预后等密切相关。阐述两种受体甲基化在子宫内膜癌组织中的研究现状，针对存在问题，提出研究方向。     

雌激素对子宫内膜癌孕激素受体亚型调控的研究

目的 研究不同剂量雌激素(雌二醇,E_2)对子宫内膜癌细胞系中孕激素受体亚型在蛋白水平的调控,探讨雌激素、孕激素受体亚型与子宫内膜癌的关系。方法 体外培养子宫内膜癌细胞系HEC-IB,分别用含5nm、10nm、20nm雌二醇的培养液分别作用于细胞24、48、72h,以不含雌二醇的培养液培养细胞为自身对照。通过Western blot方法观察不同剂量雌激素对孕激素受体亚型A、B的蛋白水平调控的动态变化,并以乳腺癌细胞系MCF-7为对照。结果 ①HEC-IB细胞分别经5nm、10nm、20nm的E_2作用24、48、72h后,与未加药的细胞相比,不同浓度、时间下E_2对hPRB调控作用均不明显;而对hPRA的作用在E_2 5um时下调,且随时间延长,下调作用越加明显;在10nm的第24、48h下降,其后渐上升,而在E_2 20nm作用72h时基本恢复加药前的水平。②MCF-7细胞分别经E_2 5nm、10nm、20nm作用24、48、72h后,与未加药的细胞相比较,各种浓度及时间下,E_2对hPRA、B有上调作用的趋势;其中10nm的E_2上调作用较为明显,各种浓度的E_2在第48h的上调作用更为显著。结论 E_2对hPR亚型的调控具有细胞特异性、时间及剂量的依赖性。HEC-IB细胞中,各种浓度、时间下E_2对hPRB调控作用均不明显;而对hPRA的调控作用具有下调的趋势。     

雌、孕激素受体亚型及其在子宫内膜癌组织中的表达

雌激素受体(ER)存在α、β两种亚型，两者在结构上虽有相似之处，但功能却不尽相同，且在各组织中的表达方式及表达量不尽相同。孕激素受体(PR)也存在A、B两种亚型。对ERα和ERβ、PRA及PRB在正常子宫内膜组织、子宫内膜癌组织中的分布及与子宫内膜癌分级的关系等方面进行简要综述。     

子宫内膜癌及癌前病变的孕激素治疗

子宫内膜癌及癌前病变的孕激素治疗天津医科大学总医院（３０００５２）糜若然瞿全新子宫内膜癌的自然发展过程被认为是长期在雌激素作用下，经过内膜增生，由上皮内癌进展为浸润癌。长期临床观察认为孕激素治疗可逆转部分子宫内膜增生性病变，尤其是单纯性增生及轻度非典...     

子宫内膜癌的孕激素治疗

孕激素治疗子宫内膜癌并非新概念。最早 195 7年Ｍｅｉｓｓｎｅｒ等在动物实验中发现外源性雌激素持续作用可致子宫内膜癌。临床发现外源性或内源性无抵抗的雌激素对子宫内膜过度刺激与子宫内膜非典型增生和子宫内膜癌有关 ,多囊卵巢综合征、分泌激素的卵巢肿瘤如卵泡膜细胞瘤和颗粒细胞瘤、ＨＲＴ使用无抵抗雌激素、他莫昔芬治疗等均可增加子宫内膜癌危险。无抵抗的雌激素使子宫内膜细胞有丝分裂活跃 ,ＤＮＡ复制错误数量增加 ,致恶性表现型的基因突变增加[1] 。同理外源性孕激素因抑制雌激素的增生作用而起治疗作用 ,最早由Ｋｉｓｔｎｅｒ…     

孕激素与子宫内膜增生和子宫内膜癌

应用孕激素可以在一定程度上抑制子宫内膜增生及子宫内膜癌的发生.孕激素广泛应用于治疗部分子宫内膜增生患者和需保留生育能力以及晚期、复发等情况的子宫内膜癌患者,取得一定疗效.阐述孕激素与子宫内膜增生、子宫内膜癌发生的关系及其治疗机理和临床应用.     

子宫内膜腺癌中孕激素受体亚型的表达

目的 研究子宫内膜癌中孕激素受体A、B、C三种亚型的表达,探讨其在子宫内膜癌发生、发展中的作用。方法 选取子宫内膜腺癌标本23例,其中高分化腺癌9例,中分化腺癌12例,低分化腺癌2例。另外选取绝经后子宫内膜标本5例。分别提取内膜或癌组织蛋白质,采用Western印迹法进行孕激素受体A、B、C三种亚型(hPRA、hPRB、hPRC)表达的半定量分析。结果 子宫内膜中、低分化腺癌与绝经后内膜对照相比,hPRB表达显著性降低(P=0.045);高分化腺癌和绝经后内膜hPRB差异无显著性(P>0.05)。中、低分化腺癌的hPRA、hPRB及hPRC低于高分化腺癌,但差异无显著性(P>0.05)。结论 子宫内膜中、低分化腺癌与绝经后内膜对照相比,hPRB显著下调,而高分化腺癌与绝经后内膜差异无显著性,提示hPBB可能与肿瘤的发生及分化程度有关。     

EGFR过表达降低人子宫内膜癌细胞孕激素敏感性的研究

目的:检测表皮生长因子受体(EGFR)基因在子宫内膜癌孕激素敏感细胞株Ishikawa及孕激素不敏感细胞株KLE的表达,探讨EGFR基因过表达对人子宫内膜癌细胞孕激素敏感性的影响。方法:实时定量PCR法和蛋白印迹法检测Ishikawa和KLE细胞中EGFR及PR-BmRNA和蛋白的表达。将EGFR全长cDNA真核表达质粒在脂质体介导下转染至Ishikawa细胞,同时以转染空载体和未转染的Ishikawa细胞为对照,分别应用实时定量PCR检测各组细胞EGFR、PR-BmRNA表达的变化,应用蛋白印迹法检测各组细胞EGFR、PR-B蛋白表达的变化;CCK-8法观察转染EGFR基因后Ishikawa细胞对孕激素敏感性的变化。结果:(1)Ishikawa细胞中,EGFRmRNA和蛋白的表达明显低于KLE细胞(P<0.001),而PR-BmRNA和蛋白的表达则显著高于KLE细胞(P<0.001);(2)稳定转染EGFR基因后,Ishikawa细胞中EGFRmRNA和蛋白的表达水平明显高于转染空载体和未转染的Ishikawa细胞(P<0.001),而PR-BmRNA和蛋白的表达水平则显著降低;(3)10-8、10-7、10-6、10-5mol/L的MPA对未转染和转染空载体的Ishikawa细胞的抑制作用显著(P<0.05),但对稳定过表达EGFR的Ishikawa细胞无明显抑制作用(P>0.05)。结论:转染EGFR基因能有效提高Ishikawa细胞内EGFR基因的表达,但可下调PR-B基因的表达使Ishikawa细胞对MPA不敏感。     

孕激素受体及B亚型在子宫内膜腺癌的表达及意义

目的 研究子宫内膜癌组织中孕激素受体及B亚型的分布及表达,探讨其临床意义。方法选取30例子宫内膜癌手术标本和10例正常增生期子宫内膜标本,石蜡切片,采用免疫组化方法,测定组织孕激素受体亚型的分布及表达。结果孕激素受体及B亚型均为核受体。PR在子宫内膜癌组织中表达的阳性率为93.33％,对照组的阳性率为100.00％,两者比较差异无显著性(P>0.05);PRB在子宫内膜癌组织中表达的阳性率为50.00％,与对照组比较差异有显著性(P<0.05)。PR的阳性率表达与分化程度无相关性,肿瘤不同分化程度的PRB阳性表达率有显著差异,分化高的:PRB阳性率高,分化低的PRB阳性率低。PR及PRB的阳性表达在临床分期I～Ⅲ各组间差异均无显著性(P值均>0.05)。结论hPR与hPRB为核受体,在子宫内膜腺癌组织中的阳性表达有所不同,PRB的阳性表达与病理分级有一定的关系,故测定PR、PRB在内膜癌的表达对指导其内分泌治疗、预测预后有一定的意义。     

子宫内膜癌中孕激素受体亚型表达及其甲基化状态的研究

目的:研究子宫内膜癌中孕激素受体亚型PRA、PRB表达与其启动子区甲基化状态的关系,探讨子宫内膜癌中孕激素受体亚型表达下调的机制。方法:(1)应用Real-Time PCR法检测子宫内膜癌及正常组织中孕激素受体亚型PRA、PRB mRNA的表达及去甲基化试剂5-Aza-CdR处理Ishikawa细胞前后孕激素两种受体亚型及DNA甲基化转移酶mRNA的表达;(2)应用甲基化特异性PCR(MS-PCR)检测子宫内膜癌细胞系Ishikawa中PRA、PRB的甲基化状态。结果:与正常子宫内膜组织比较,子宫内膜癌组织中,总PR表达显著降低,与病理类型相关;PRB表达显著下降,与其临床特征无关。子宫内膜癌细胞系Ishikawa中,加入5-Aza-CdR2.5μmol/L48h后,孕激素受体亚型PRA、PRB甲基化条带均消失;孕激素受体亚型PRA、PRB mRNA表达水平增加;同时Ishikawa细胞中DNA甲基转移酶DNMT1、DNMT3B表达下调。结论:子宫内膜癌组织中,孕激素受体亚型mRNA表达下调可能与子宫内膜癌的发生相关;孕激素受体亚型表达下调与其启动子区甲基化状态相关;去甲基化试剂5-Aza-CdR可逆转基因启动子区的甲基化状态,恢复PR基因的表达。     

Hormone receptor expression patterns in the endometrium of asymptomatic morbidly obese women before and after bariatric surgery

Objective

Obesity increases risk for endometrial neoplasia, but neither the pathophysiology nor the effects of weight loss on the risk are well established. We attempted to characterize the molecular profile of the endometrium of asymptomatic women with morbid obesity before and following bariatric surgery-induced weight loss.

Methods

59 asymptomatic, morbidly obese women underwent endometrial sampling before bariatric surgery; 46 (78%) of these returned one year later for re-biopsy (median weight loss of 41 kg). Duplicate samples from these specimens were scored for expression of estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), and Ki-67 by two independent, blinded pathologists using an H-score [staining intensity (0–3) × (percent of tissue involved)].

Results

The prevalence of hyperplasia pre-operatively was 7% overall and 10% among patients not on an anti-estrogen. ER H-scores were similar before and after surgery overall (median 190 and 196 respectively, p = 0.82), but patients with hyperplasia had higher pre-operative H-scores (median 256, p < 0.001) and experienced greater H-score drops, than those without hyperplasia (− 112 vs + 50, p = 0.028). In two patients with persistent hyperplasia at one year, ER H-scores fell to levels that were similar to those without pathology. One patient who developed hyperplasia during the study period had a rising ER H-score. Patients with hyperplasia had higher median PR H-scores pre-operatively (284 vs 188, p = 0.01), which normalized through greater drops (75 vs 0, p = 0.053). AR H-scores dropped significantly after surgery (13 vs 2, p = 0.015), but were similar between patients with and without hyperplasia (p = 0.33). Weight loss did not affect Ki-67 proliferation index.

Conclusion

Asymptomatic morbidly obese patients have a high prevalence of occult hyperplasia, characterized by relatively high hormone receptor expression. These profiles appear to normalize with weight loss and in advance of pathologically identifiable changes. These data suggest a potential role for screening this population as well as the possibility that weight loss may be a valid treatment strategy for risk reduction.     

Changes in glandular and stromal estrogen and progesterone receptor isoform expression in eutopic and ectopic endometrium following treatment with the levonorgestrel-releasing intrauterine system

Objectives

The levonorgestrel (LNG) intrauterine system (LNG-IUS) has been shown to improve symptoms in women with minimal to moderate endometriosis. The precise mechanism for this is unknown. We hypothesized that this involves alteration in the expression of estrogen receptors (ER) and progesterone receptors (PR).

Study design

A prospective study of tissues obtained prospectively from 28 women with laparoscopically confirmed minimal to moderate endometriosis treated with LNG-IUS for 6 months. Endometrial and endometriotic biopsies obtained before and 6 months after treatment were processed and stained for ER-α, ER-β and PR expression by immunohistochemistry. Photographs were obtained and the receptors quantified.

Results

The mean (±SD) age of the 28 women was 31 ± 7.2 (range 18-42) years. Eight of them at initial biopsy were in the proliferative phase and 20 in the secretory phase. ER-α, ER-β and PR expression decreased significantly in the glandular (P < 0.0001) and stromal (P < 0.0001) compartments of the eutopic endometrium after treatment with LNG-IUS. Similarly, ER-α, ER-β and PR were significantly decreased in the stromal compartment of ectopic endometrium (P < 0.0001), and significantly decreased in the ectopic glands of ER-α (P < 0.0001), ER-β (P = 0.0002) and PR (P = 0.0064) expression.

Conclusion

The ameliorative effect of LNG-IUS on the symptoms of minimal to moderate endometriosis is likely modulated through a decrease in the expression of glandular and stromal ER-α, ER-β and PR in the ectopic endometrium.     

Heparanase expression increases throughout the endometrial hyperplasia-cancer sequence.

OBJECTIVE: To assess the expression of heparanase in the different stages leading to endometrial cancer. METHODS: The 38 examined specimens included adenocarcinoma, hyperplasia, and normal endometrium specimens. Heparanase, estrogen, and progesterone receptor expressions were analyzed immunohistochemically and the intensity was scored. RESULTS: Secretory normal endometrium and simple hyperplasia specimens expressed the lowest mean values of expression (1.00 and 0.63, respectively); the complex hyperplasia specimens and G2 endometrioid adenocarcinoma showed the highest values of expression (2.33 and 2.71, respectively). A linear trend (P=0.005) of heparanase expression was observed when comparing the normal endometrium and simple hyperplasia group with the complex hyperplasia+G1 carcinoma group and the G2+G3 carcinoma group. Evaluation of atrophic and inactive endometrium compared with papillary serous carcinomas yielded no significant differences. We found no significant correlation between heparanase expression and estrogen receptor or progesterone receptor expression. CONCLUSION: Heparanase expression was tightly regulated in endometrial tumorigenesis.     

雌、孕激素受体、生长激素受体、胰岛素样生长因子1受体与子宫内膜容受性的关系

辅助生殖技术(ART)经过近40年的发展,已取得突飞猛进的进展。但是临床妊娠率仍然徘徊在30%~40%。决定能否成功妊娠的因素主要包括2个方面,一是胚胎发育的质量,二是子宫内膜对胚胎的容受性。而在临床工作中,即使胚胎质量良好,种植率仍然不能令人满意。因此,如何提高子宫内膜容受性已经成为辅助生殖领域一个亟待解决的问题,了解影响子宫内膜容受性的相关因素,对于在种植窗期如何调节母体的内膜达到最佳的接纳胚胎的状态,具有重要的指导性意义。本文着重阐述子宫内膜容受性与雌激素受体(ER)、孕激素受体(PR)、胰岛素样生长因子1受体(IGF-1R)、生长激素受体(GHR)之间的关系,期望对临床判断子宫内膜容受性有所帮助。