雌激素膜受体GPR30在子宫内膜癌的表达及意义

目的:探讨雌激素膜受体GPR30在子宫内膜癌的表达及意义。方法:RT-PCR和免疫组织化学法检测子宫内膜癌组织和正常子宫内膜组织中GPR30mRNA和蛋白的表达,分析GPR30表达与临床病理的联系;免疫细胞化学分析GPR30蛋白在子宫内膜癌细胞系RL95-2(ER+)和KLE(ER-)的表达。结果:子宫内膜癌组织GPR30mRNA的表达水平显著高于正常子宫内膜组织(P<0.05);子宫内膜癌组织GPR30蛋白表达阳性率(21/30,70%)显著高于正常子宫内膜组织(5/17,29.41%)(χ2=7.232,P=0.007);肿瘤组织学分级越高,GPR30表达阳性率越高(P=0.003),GPR30表达与内膜癌分期、肌层浸润深度和腹水转移无关(P>0.05);ERα阳性的子宫内膜癌细胞系RL95-2和ERα阴性的细胞系KLE均表达GPR30。结论:雌激素膜受体GPR30于子宫内膜癌组织和子宫内膜癌细胞系均有表达,与肿瘤组织学高分级相关,提示GPR30可能在子宫内膜癌中发挥重要的作用。     

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。     

雌激素受体亚型mRNA在子宫内膜癌组织中的表达

目的比较雌激素受体两种亚型α和β在子宫内膜癌中的表达,探讨雌激素受体亚型在子宫内膜癌发生和发展中的作用.方法用RT - PCR法检测子宫内膜癌和正常子宫内膜组织雌激素受体mRNA的表达.结果①与正常子宫内膜组织比较,子宫内膜癌中ER α mRNA、ER β mRNA表达和ER β/ER α mRNA比值都明显上升;②早期、内膜样子宫内膜癌ER α mRNA明显上升.结论子宫内膜癌的发生与ER α和ER β的表达有关,ER α mRNA表达升高可能提示子宫内膜癌预后较好.     

Immunohistochemical determination of estrogen and progesterone receptors and DNA flow cytometry in endometrial cancer

Estrogen and progesterone receptor contents (ER, PR) were assessed by an immunohistochemical method and DNA ploidy and S-phase by flow cytometry in frozen endometrial cancer tissue sections from 39 cases. Comparison of the immunohistochemical and cytosol assays showed 81% and 84% concordance in ER and PR contents, respectively. An aneuploid DNA pattern was identified in 30% and a high S-phase fraction was found in 33% of 36 specimens studied. Negative ER status was associated with aneuploid and high S-phase fraction. A similar association was found between PR status and high S-phase fraction. Combined analysis of immunohistochemical receptor status and DNA flow cytometry in the same sample makes it possible to identify two strong predictive factors in endometrial adenocarcinoma.     

基质金属蛋白酶-2及孕激素受体在子宫内膜癌组织中的表达及其意义

目的检测基质金属蛋白酶-2（MMP-2）和孕激素受体（PR）在子宫内膜癌组织中的表达，分析其在子宫内膜癌中表达的相关性以及与临床病理特征的关系，探讨MMP-2在子宫内膜癌发生、发展中的作用。方法采用免疫组化SP法检测45例子宫内膜癌和12例增生子宫内膜中MMP-2、PR的表达，以20例正常子宫内膜作为对照。结果MMP-2蛋白在正常子宫内膜、增生子宫内膜中的阳性表达率比较，差异无显著性（P〉0．05）。子宫内膜癌组织中MMP-2阳性表达率（62．2％）高于对照组（15．6％）（P〈0．05）。MMP-2在中、低分化子宫内膜癌组织中的阳性表达率（82．6％）高于高分化子宫内膜癌组织（40．9％）（P〈0．01），有肌层浸润标本中的阳性表达率（71．1％）高于无肌层浸润者（14．3％）（P〈0．05）；绝经者（65．5％）与未绝经者（56．3％）、手术病理为Ⅰ期者（52．0％）与Ⅱ～Ⅳ者（75．0％）以及有淋巴结转移者（63．6％）与无淋巴结转移者（61．8％）相比，MMP-2的阳性表达率差异无显著性。子宫内膜癌中PR的阳性表达率（55．6％）明显低于对照组（84．4％）（P〈0．05）。MMP-2与PR在子宫内膜癌中的表达呈负相关（P=0．0048，r=-0．42）。结论MMP-2在子宫内膜癌中呈高表达，可能在其进展中有重要作用，PR表达降低可能是MMP-2表达升高的原因；检测MMP-2在子宫内膜癌中的表达，有助于子宫内膜癌预后的判断。     

雌激素跨膜受体GPR30介导子宫内膜癌中IL-6/STAT3炎症信号通路的激活

目的:探讨新型雌激素跨膜受体GPR30对子宫内膜癌中IL-6/STAT3炎症信号通路的调节作用。方法:将子宫内膜癌细胞系Ishikawa、KLE分为5组:对照组、E2组、G1组(GPR30特异性激动剂)、E2+G15组(GPR30特异性抑制剂)、G1+G15组。应用转染技术下调Ishikawa和KLE细胞中GPR30的表达后,分别给予E2和G1作用。Western blot法检测各组细胞中STAT3的蛋白表达水平;ELISA法检测细胞培养上清中IL-6的含量。结果:Ishikawa、KLE细胞系中E2组和G1组的STAT3蛋白及IL-6表达水平均显著高于对照组、E2+G15组、G1+G15组(P<0.05)。GPR30稳定下调后,E2+RNAi组和G1+RNAi组中STAT3蛋白与IL-6表达上调均被阻断(P<0.05)。结论:E2和G1能促进子宫内膜癌细胞中IL-6/STAT3的表达,GPR30的表达下调和阻滞剂能抑制E2和G1诱导的子宫内膜癌细胞IL-6/STAT3的表达。GPR30可通过激活IL-6/STAT3炎症通路而在子宫内膜癌组织中发挥重要作用。     

子宫内膜癌分子标志物与临床病理特征关系的研究

目的探讨子宫内膜癌中ER、PR、PTEN、p53及Ki-67的表达与临床、病理特征的关系。方法收集200例原发性子宫内膜癌患者的临床病理资料,对其ER、PR、PTEN、p53及Ki-67表达情况进行统计学分析。结果①子宫内膜癌病例中．ER、PR、PTEN、p53的阳性表达率分别为86．5％、85．5％、82．10和49．2％;Ki-67在癌灶中的阳性表达率为4％--95％,平均为46．9％。②妊娠次数与PR阳性表达呈负相关（r=-0．191,P=0．007）,而发病年龄、分娩次数与p53阳性表达呈正相关（r=0．184,P=0．041;r=0．255,P=0．004）。③子宫内膜样腺癌ER、PR、p53阳性率与其他类型子宫内膜癌比较,差异有统计学意义（P〈0,01）。④ER阳性表达与手术病理分期呈负相关（r=-0．155,P=0．028）,其中I期患者ER阳性率高于Ⅱ期及以上患者（P=0．032）。⑤ER、PR阳性表达与组织学分级呈负相关（r=-0．217,P=0．002;r=-0．317,P=0．000）,但p53、Ki-67表达与其呈正相关（r=0．327,P=0．000;r=0．465,P=0．000）。⑥ER阳性表达与肌层浸润深度呈负相关（r=-0．142,P=0．046）,在有无深肌层浸润上ER、PR表达率均有统计学意义（P〈0．05）。结论对子宫内膜活检组织进行分子标志物的分子特征检测,有助于指导临床。     

Recurrent endometrial carcinoma regression with the use of the aromatase inhibitor anastrozole

Recurrent/metastatic endometrial adenocarcinoma that is not amenable to cure with local or regional therapy and/or chemotherapy represents a discouraging clinical entity for the clinician. We report the case of 58-year-old woman with recurrent endometrial carcinoma that was resistant to chemotherapy that was treated successfully with the aromatase inhibitor anastrozole.     

子宫内膜癌细胞系Ishikawa和HEC-1A细胞雌激素受体表达

目的研究子宫内膜癌细胞系Ishikawa和HEC-1A雌激素受体(ER)的表达情况。方法应用免疫细胞化学和逆转录酶-多聚酶链反应(RT-PCR)技术,检测Ishikawa和HEC-1A细胞中ERα、ERβ蛋白和mRNA表达水平。结果Ishikawa细胞中,ERα、ERβ蛋白均呈阳性表达,而在HEC-1A细胞中ERα呈弱阳性表达,ERβ阴性表达;Ishikawa细胞中ERα、ERβmRNA表达水平均显著高于HEC-1A细胞;(P<0.01)。结论Ishikawa细胞是ER阳性子宫内膜癌细胞系,而HEC-1A细胞则为ER低表达细胞系。     

Angiogenesis factor in endometrial carcinoma: A new prognostic indicator?

OBJECTIVE: Tumor angiogenesis is believed to be a prognostic indicator associated with tumor growth and metastasis. Studies of angiogenesis in breast, prostate, and lung cancer, as well as melanoma, have shown that neovascularization correlates with the likelihood of metastasis and recurrences. The purpose of this study was to evaluate microvessel density as a prognostic factor in endometrial cancer. METHODS: Between 1980 and 1991 the tumor registry identified 25 patients with a diagnosis of recurrent endometrial cancer. These patients were matched with 25 patients with nonrecurrent disease for age, stage, grade, and treatment. The histologic slides of the 50 patients were reviewed. The paraffin blocks were obtained, and the area of the deepest myometrial invasion was selected for staining. The microvessels within the invasive cancer were highlighted by means of immunocytochemical staining to detect factor VIII - related antigen. Microvessels were counted by two investigators who were blinded to the patients' clinical status. Survival data were analyzed with Kaplan-Meier survival curves. RESULTS: Microvessel count was related to likelihood of recurrence, although this trend did not reach statistical significance. Patients with tumors of low capillary density had a mean survival time of 123 months. Patients with tumors of high capillary density had a mean survival time of 75 months (p = 002). Among patients with recurrent disease, those with a low capillary count survived a mean of 64 months. Patients with recurrent disease with tumors of high capillary density survived a mean of 45 months (p = 0.002). CONCLUSION: Angiogenesis factor correlates with survival in endometrial carcinoma. (Am J Obstet Gynecol 1996;174:1879-84.)     

Utility of MIB-1 and estrogen and progesterone receptor in distinguishing between endometrial stromal sarcomas and endometrial stromal nodules, highly cellular leiomyomas

It is difficult to differentiate between an endometrial stromal nodule (ESN) and endometrial stromal sarcoma (ESS) in curettage specimen, and the recommended therapy of endometrial stromal neoplasm is hysterectomy. If we could discriminate ESS from ESN in curettage specimens, there would be an opportunity to treat ESN by local excision rather than by hysterectomy. We analyzed MIB-1 and estrogen and progesterone receptor (ER/PR) expression in a retrospective series of 8 ESSs, 7 ESNs, and 17 highly cellular leiomyomas obtained from hysterectomy specimens. ESSs expressed MIB-1 more frequently than ESNs (P < 0.05), and ESSs had a tendency to express ER less frequently than ESNs (P= 0.08). We observed that in spite of showing MIB-1 expression to some extent, highly cellular leiomyomas usually could not reach ESSs' level and frequency of MIB-1 expression in the current study. Although MIB-1 and ER appear to be promising markers in the differential diagnosis of ESSs, a larger study would be necessary to confirm their validity.     

Function of estrogen receptor isoforms α and β in endometrial carcinoma cells

The aim of this study was to explore how to modulate the expression of estrogen receptors (ER) alpha and beta and to verify the role of ERalpha and beta in relationship to estrogen and tamoxifen (TAM). A series of oligodeoxyribonucleotides (ODN) corresponding to regions of the ERalpha or beta was tested in human endometrial cancer cell lines (HEC-1B). The change in HEC-1B proliferation in response to 17beta-estradiol (E(2)) and TAM under the impact of antisense ODN was studied. The results of the study are as follows: 1) transfection with antisense ODN significantly inhibited ERalpha and ERbeta protein production, 2) the cells lost the ability to proliferate in response to E(2) after transfection with ERalpha antisense ODN especially at 24, 48, and 72 h. There was no obvious change in response to E(2) in HEC-1B cell lines that were transfected with ERbeta antisense ODN, and 3) after transfection with ERalpha antisense ODN, HEC-1B cells lost the ability to proliferate in response to TAM at 48 h. This inhibition was also observed after transfection with ERbeta antisense ODN at 24 h. ERalpha may be the primary receptor in the proliferation of HEC-1B cells in response to E(2). Both ERalpha and ERbeta are involved in the agonist impact of TAM on endometrial cancer cells.     

CYP1A1 gene polymorphism and risk of endometrial hyperplasia and endometrial carcinoma

The cytochrome P4501A1 (CYP1A1) is involved in the metabolism of environmental carcinogens and estrogen. We hypothesized that CYP1A1 genetic polymorphism may be a susceptibility factor for endometrial hyperplasia (EH) and endometrial carcinoma (ECa). We therefore evaluated this hypothesis in patients with EH and ECa and control subjects using allele-specific polymerase chain reaction-based method in a Turkish population. The patients with CYP1A1 Ile/Val genotype had a fivefold higher risk of having EH than those with Ile/Ile. In contrast, a higher frequency of any Val genotype (Ile/Val and Val/Val) was found in patients with EH, indicating that persons carrying any Val allele are at increased risk for developing EH. In the ECa group, patients were also more likely to have CYP1A1 Ile/Val allele, with an adjusted odds ratio of 3.0. Moreover, there was a statistically significant increase in relative risk association with any Val genotype between patients and controls, suggesting that individuals carrying any Val genotype are at increased risk for developing ECa. We concluded that variant alleles of the CYP1A1 gene might be associated with EH and ECa susceptibility. Further studies with a large sample size should be considered to address issues of interactions between CYP1A1 and other risk factors.     

G蛋白耦联受体30(GPR30)在上皮性卵巢癌中的表达与增殖相关基因c-fos、cyclinD1表达的相关性

目的:探索新型雌激素受体G蛋白耦联受体30(G protein coupled receptor 30,GPR30)在人上皮性卵巢癌发生发展中的作用。方法:采用免疫组织化学SP法检测30例上皮性卵巢癌组织中GPR30、增殖相关基因c-fos和cyclinD1的表达,并以9例良性卵巢肿瘤、4例正常卵巢组织作对照。结果:GPR30在上皮性卵巢癌的表达水平(80.0%)显著高于良性卵巢肿瘤(44.4%)和正常卵巢组织(25.0%)(P<0.01;P<0.05)。GPR30和c-fos的表达与上皮性卵巢癌的病理类型、FIGO分期有关,在浆液性囊腺癌、FIGOⅢ-Ⅳ期的表达水平显著升高(P<0.05)。未见cyclinD1的表达与上皮性卵巢癌临床病理参数的关系(P>0.05)。上皮性卵巢癌中GPR30与c-fos、cyclinD1的表达具有正相关性(P<0.01;P<0.05)。结论:GPR30可能通过c-fos、cyclinD1促进卵巢癌增殖,参与上皮性卵巢癌的发生、发展。     

Clinicopathologic study of uterine endometrial carcinoma in young women aged 40 years and younger

To clarify what constitutes the adequate management of uterine endometrial carcinoma in young women, we reviewed clinicopathologically 31 patients aged 40 years and younger between January 1991 and June 2004. As a primary treatment, 12 cases chose hormonal treatment with medroxyprogesterone acetate (MPA; 600 mg/day) due to no findings of myometrial invasion and diagnosis of a grade 1, well-differentiated adenocarcinoma. In remaining 19 cases, surgery was performed. All the 19 patients who received surgery as a primary treatment are alive, with no evidence of a recurrence of the disease. In the 12 patients who received hormonal treatment, 8 patients eventually received a hysterectomy because of recurrence or no response to MPA. Of these eight patients, myometrial invasion was recognized in three patients. One of the eight patients died of the metastasized disease to the liver and brain after hysterectomy. After hormonal treatment, 4 of the 12 patients were exempted from surgery and showed no evidence of recurrence. Two patients had viable children. Progesterone receptor was negative in one case that died. Careful consideration should be given to hormonal treatment with MPA for the conservative management of endometrial carcinoma in young women. Moreover, MPA is not always a consistent management for every patient.     

雌激素硫酸转移酶与甾体硫酸酯酶在子宫内膜癌中的表达

目的探讨雌激素硫酸转移酶(estrogen sulfotransferase,EST)和甾体硫酸酯酶(steroid sul-fatase,STS)在子宫内膜癌中的表达。方法采用免疫组化检测100例子宫内膜癌组织中EST和STS表达水平;RT-PCR检测35例子宫内膜癌组织EST mRNA和STS mRNA表达水平。并选择同期10例其他原因子宫切除患者作为对照组。结果对照组子宫内膜中,EST蛋白阳性表达率为90%(9/10),STS蛋白无表达;子宫内膜癌中,EST蛋白阳性表达率为53%(53/100),STS蛋白阳性表达率57%(57/100)。子宫内膜癌组EST蛋白和STS蛋白阳性表达与对照组比较,差异有统计学意义(P0.05)。与对照组比较,子宫内膜癌组EST mR-NA均值下降,STS mRNA、STS mRNA/EST mRNA的均值上升(P0.05)。结论子宫内膜癌的发病可能与EST、STS的表达及STS/EST的变化有关。