Expression of platelet-derived endothelial cell growth factor (PD-ECGF) and its mRNA in uterine endometrial cancers

To determine the potential of growth, invasion and metastasis of uterine endometrial cancer cells associated with neovascularization, the expressions of platelet-derived endothelial cell growth factor (PD-ECGF) and its mRNA in uterine endometrial cancers and in normal uterine endometria as controls were determined and the relationship between their expressions and histological grades, grades of myometrial invasion and clinical stages of uterine endometrial cancers was analyzed. The levels of PD-ECGF were significantly higher in uterine endometrial cancers of well-differentiated grade (G1) with invasion to ≤1/2 myometrium (B) and of stage I than in those of moderately and poorly differentiated grades (G2 and G3, respectively) limited to endometrium (A) and with invasion to >1/2 myometrium (C) and of stages II and III/IV and in normal uterine endometria. There was no significant difference in the levels between uterine endometrial cancers of G2 and G3, A and C, or stages II and III/IV and normal uterine endometria. Therefore, the active availability of PD-ECGF might contribute to the acceleration of angiogenic activity in the early process of invasion of well-differentiated uterine endometrial cancers.     

Expression of protease activated receptor-2 related to angiogenesis in tumor advancement of uterine endometrial cancers

Protease activated receptor-2 (PAR-2) is the second member of a novel family of G-protein coupled seven-transmembrane domain receptors. PAR-2 has been reported to be expressed in various tumors and play a vital role in the regulation of cancer cell growth. The purpose of this study was to clarify the roles of PAR-2 in the angiogenic pathway in uterine endometrial cancers. PAR-2 expression was analyzed in 61 uterine endometrial cancer and 15 normal endometrium tissue specimens. PAR-2 histoscores and mRNA levels were determined by immunohistochemistry and real-time RT-PCR, respectively. Microvessel counts were determined by immunohistochemistry for CD31 and factor VIII-related antigen. The localization of PAR-2 was dominant in the cancer cells of endometrial cancer tissues of all cases studied. PAR-2 histoscores highly correlated with PAR-2 mRNA levels in the same tissues (r=0.87, p<0.001). PAR-2 histoscores and mRNA levels both significantly increased in uterine endometrial cancers with clinical stages (I相似文献   

Clinical implications of the expression of estrogen receptor-alpha and -beta in primary and metastatic lesions of uterine endometrial cancers

Novel human estrogen receptor (ER)-beta was identified in cDNA libraries from human testes. ER-beta specifically expresses in the testis, ovary, thymus, spleen, osteoblasts, fetus and uterine endometrium. ER-beta might not conserve the same physiological functions as does ER-alpha. Therefore, expressions of ER-alpha and ER-beta mRNAs in primary and metastatic lesions of uterine endometrial cancers were investigated. The levels of ER-beta mRNA were significantly lower than those of ER-alpha mRNA in uterine endometrial cancers and in normal uterine endometria. The ratio of ER-beta to ER-alpha mRNA in most primary uterine endometrial cancers was similar to that in normal uterine endometria (<0.4% of ER-beta mRNA to ER-alpha mRNA). On the other hand, in 14 of the 20 lymph node metastasis-positive cases of uterine endometrial cancers, the ratio in the metastatic lesion was significantly higher than that in the primary lesion of the corresponding case, and patient prognosis in these cases was extremely poor. Therefore, it is suggested that the intact synchronized expression of ER-beta interacting with ER-alpha might be disrupted, especially in most metastases of uterine endometrial cancers, leading to poor patient prognosis related to estrogen refractoriness.     

Overexpression of ephrinB2 and EphB4 in tumor advancement of uterine endometrial cancers.

BACKGROUND: The ligand ephrinB2 and the corresponding receptor EphB4 contribute to tumor growth in various human tumors. This prompted us to study the expression and localization of ephrinB2 and EphB4 in uterine endometrial cancers to analyze the ephrinB2/EphB4 functions against clinical backgrounds. MATERIALS AND METHODS: We carried out immunohistochemistry and real-time RT-PCR to determine the histoscores and messenger RNA (mRNA) levels of ephrinB2 and EphB4, respectively, in 68 uterine endometrial cancers and 16 normal endometrium tissue samples. Patient prognoses were analyzed with a 60-month survival rate. RESULTS: The localization of ephrinB2 and EphB4 was dominantly in the cancer cells of uterine endometrial cancer of all cases given. EphrinB2 and EphB4 histoscores were highly correlated with ephrinB2 and EphB4 mRNA levels, respectively (r = 0.864 and r = 0.615, P < 0.01). Both the histoscores and mRNA levels of ephrinB2 and EphB4 significantly increased with clinical stages (I < II < III, P < 0.01), dedifferentiation (G(1) < G(2) < G(3), P < 0.01) and myometrial invasion (A < B < C, P < 0.01 for ephrinB2 and P < 0.05 for EphB4) in uterine endometrial cancers. The 60-month survival rates of the 34 patients with high ephrinB2 and EphB4 expression were poor (59% and 62% respectively), while for the other 34 patients with low ephrinB2 and EphB4 expression, they were significantly higher (85% and 82%, respectively). CONCLUSIONS: EphrinB2 and EphB4 were overexpressed during the tumor advancement as dedifferentiation and myometrial invasion. Therefore, ephrinB2/EphB4 might work on tumor advancement and may be recognized as a novel prognostic indicator for uterine endometrial cancers.     

Expression and intracellular localization of Smad proteins in human endometrial cancer

The aim of our study was to examine expression of Smad proteins i.e., Smad2, Smad3 and Smad4 both as mRNA and protein as well as their intracellular localization in normal (n=13) and neoplastic (n=42) endometrial tissue specimens using RT-PCR and immunological techniques i.e., Western blot and ELISA. Two uncommon female genital tract tumours, rhabdomyosarcoma of uterine of the cervix and uterine carcinosarcoma were also included. No statistically significant differences were found in the mRNA level of the examined Smad proteins between normal and tumour tissue specimens. Smad2 and Smad3 mRNAs were detected both in uterine carcinosarcoma and rhabdomyosarcoma of the uterine cervix. However, significantly lower Smad2 and Smad4 mRNA level was noted when the depth of myometrial invasion was considered (p<0.05). In endometrial cancer as compared to normal endometrium significantly higher levels of Smad2 and Smad3 proteins, both in cytoplasmic (p=0.002; p=0.0001) and nuclear (p=0.016; p=0.0004) fractions were observed. Both in uterine carcinosarcoma and rhabdomyosarcoma of the uterine cervix Smad2, Smad3 and Smad4 proteins were not detected. Moreover, significantly elevated Smad4 protein level in cytoplasmic fraction was stated when tumour grade and depth of myometrial invasion was undertaken (p<0.05). When intracellular distribution of Smads was considered differences between cytoplasmic and nuclear localization in normal and carcinomatous endometrium was stated. In endometrial cancer decreased number of cases with Smad3 and increased number of cases with Smad4 located in nuclear fraction was found. In conclusion, the disturbances in Smad protein expression and/or differences in their intracellular distribution suggest, that TGF-beta signaling pathway via Smads may be deregulated in endometrial carcinomas.     

Importin 13在子宫内膜异位症和子宫内膜癌中的表达及意义

背景与目的:正常情况下的子宫内膜干/祖细胞有助于子宫内膜的生理性修复,而子宫内膜干/祖细胞的异常增殖和异常分化则会导致子宫内膜疾病(如子宫内膜异位症和子宫内膜癌)。Importin 13(IPO13)是importinβ家族新成员的一个核质双向的转运受体蛋白,是角膜上皮干细胞的一个标记,在维持干细胞的性状、高增殖潜力、低分化状态,调节细胞分化以及小鼠生殖细胞减数分裂上具有重要的作用。本文探讨成体干细胞标记IPO13在子宫内膜异位症和子宫内膜癌中的表达及意义。方法:手术取正常子宫内膜组织40例(对照组),其中增生期和分泌期各20例,异位子宫内膜组织20例(异位症组)和子宫内膜癌病灶组织20例(内膜癌组)。采用免疫组化SP法检测IPO13蛋白在细胞内的定位;采用实时荧光定量PCR技术(real-time quantitativepolymerase chain reaction,RT-PCR)检测IPO13 mRNA的表达;Western blot检测IPO13蛋白的表达。结果:IPO13蛋白在内膜癌、异位症及正常对照组中腺上皮细胞和间质细胞的细胞质和细胞核中均有表达。IPO13蛋白在对照组增生期表达量(0.52±0.30)明显高于分泌期(0.25±0.04,P<0.05);IPO13蛋白在异位症组表达量(0.81±0.12)明显高于对照组增生期及分泌期(P<0.05);IPO13蛋白在内膜癌组表达量(1.21±0.11)明显高于异位症组(P<0.05)。IPO13 mRNA在对照组增生期表达量是分泌期的3倍(P<0.05);IPO13 mRNA在异位症组中表达量是对照组分泌期的6倍(P<0.05),增生期的2.5倍(P<0.05);IPO13 mRNA在内膜癌组表达量是异位症组的2倍(P<0.05)。结论:IPO13在子宫内膜癌中及异位症组中表达明显高于对照组,推测其高表达与子宫内膜癌及子宫内膜异位症发病密切相关。     

Coexpression of growth arrest-specific gene 6 and receptor tyrosine kinases Axl and Sky in human uterine endometrial cancers.

BACKGROUND: Gas6, the protein product of the growth arrest-specific gene 6 (gas6), a member of the vitamin K-dependent protein family, was identified as a ligand for the Axl/Sky family of receptor tyrosine kinases. Gas6 acts as a growth-potentiating factor for thrombin-induced proliferation of vascular smooth muscle cells. The aim of the present study was to test for the presence of Gas6 and its receptors Axl and Sky, related to specific growth in uterine endometrial cancers, and to evaluate their plausible growth potential and mechanism. MATERIALS AND METHODS: Sixty patients underwent curative resection for uterine endometrial cancers. In uterine endometrial cancers, the mRNA levels and histoscores of Gas6, Axl and Sky were determined by competitive RT-PCR using recombinant RNA and immunohistochemical studies, respectively. The rate of proliferation by immunochemistry for Ki67 and the rate of apoptosis by TUNEL were determined. RESULTS: The mRNA levels and the histoscores of Gas6 and Axl in well-differentiated endometrial cancers (G1 EC) were significantly higher than in normal uterine endometrium (NE) and in moderately and poorly differentiated endometrial cancers (G2 + G3 EC). The rate of apoptosis in G1 EC was significantly lower than that in NE and in G2 + G3 EC. CONCLUSIONS: Gas6 and Axl signal transduction is aberrantly stimulated in well-differentiated endometrial cancers, plausibly related to tumor progression due to protection from apoptosis in cancers cells.     

ERRγ在子宫内膜癌组织中的表达及临床意义

目的:探讨雌激素受体相关受体γ(estrogen receptor-related receptorsγ,ERRγ)在子宫内膜癌组织中的表达及其临床意义。方法:采用免疫组织化学链霉菌抗生物素蛋白过氧化物酶(SP)法检测40例子宫内膜癌组织及20例正常子宫内膜组织ERRγ和ERα蛋白的表达。采用Real-time PCR方法检测40例子宫内膜癌组织ERRγmRNA的表达水平,分析其与临床病理特征的关系。结果:ERRγmRNA和蛋白的表达在子宫内膜癌组织中均高于正常子宫内膜组织,差异有统计学意义(P<0.05);ERRγmRNA在子宫内膜癌中的表达与各临床病理特征之间无关(P>0.05)。然而ERRγmRNA在ERα阳性的子宫内膜癌中的表达水平与肌层浸润程度有关,差异有统计学意义(P<0.05)。结论:ERRγ子宫内膜癌中呈现高表达,且表达水平与肌层浸润程度有关,提示ERRγ对子宫内膜癌的发生发展起促进作用。     

Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGF receptor 3, as a prognostic factor in endometrial carcinoma.

PURPOSE: To evaluate the prognostic value of vascular endothelial growth factor (VEGF)-D and VEGF receptor (VEGFR)-3 in endometrial carcinoma. EXPERIMENTAL DESIGN: We assessed the levels of immunoreactivity for VEGF-D and VEGFR-3 in 71 endometrial carcinomas, 14 complex atypical endometrial hyperplasias, and 16 normal endometria by immunohistochemistry. RESULTS: VEGF-D was stained in both tumor cells and adjacent stromal cells. VEGFR-3 was stained in both tumor cells and adjacent endothelial cells. Immunoreactivity for VEGF-D in tumor cells and adjacent stromal cells became significantly stronger as lesions progressed from normal endometrium to advanced carcinoma. Similarly, immunoreactivity for VEGFR-3 in tumor cells and adjacent endothelial cells was significantly greater as lesions progressed from normal endometrium to advanced carcinoma. A strong correlation was found between high levels of VEGF-D immunoreactivity in carcinoma cells and VEGFR-3 in both carcinoma cells and adjacent endothelial cells. Similarly, high levels of VEGF-D immunoreactivity in stromal cells were significantly correlated with those of VEGFR-3 in both carcinoma cells and endothelial cells. High levels of VEGF-D in carcinoma cells and stromal cells, as well as those of VEGFR-3 in carcinoma cells and endothelial cells, were significantly related to myometrial invasion and lymph node metastasis. A strong correlation was found between poor survival and high levels of VEGF-D in both carcinoma cells and stromal cells and between poor survival and high levels of VEGFR-3 in carcinoma cells. Moreover, the high levels of VEGF-D in stromal cells and VEGFR-3 in carcinoma cells were independent prognostic factors in endometrial carcinoma. CONCLUSIONS: The presence of VEGF-D and VEGFR-3 in endometrial carcinoma may predict myometrial invasion and lymph node metastasis and may prospectively identify patients who are at increased risk for poor outcome. In addition, VEGF-D and VEGFR-3 may be promising targets for new therapeutic strategies in endometrial carcinoma.     

KISS-1 mRNA和GPR54 mRNA在子宫内膜癌中的表达及意义

目的　检测KISS- 1mRNA和GPR5 4mRNA在子宫内膜癌组织中的表达,探讨其在子宫内膜癌侵袭及转移中的作用。方法　采用逆转录多聚酶链反应(RT PCR)法,检测32例子宫内膜癌、1 0例子宫内膜上皮内瘤样病变(EIN)和1 2例正常子宫内膜组织中KISS -1mRNA和GPR5 4mRNA的表达情况,分析其与各种临床参数的关系。结果　子宫内膜癌患者的KISS 1mRNA表达率(37.5 %)明显低于EIN者(80 .0 %)和正常内膜者(83.3%) ,其在子宫内膜癌组中的表达与临床分期、肌层侵袭深度及淋巴结转移密切相关(P均<0 .0 5 )。子宫内膜癌患者的GPR5 4mRNA表达率(78.1 %)高于EIN者(70 .0 %)和正常内膜者(6 6 .7%) ,但差异无统计学意义(P均>0 .0 5 )。GPR5 4mRNA在子宫内膜癌中的表达与临床分期、组织学分级、肌层侵袭深度及淋巴结转移情况均无相关性(P均>0 .0 5 )。结论KISS -1与其受体GPR5 4结合在抑制子宫内膜癌的侵袭和转移过程中可能起着重要的作用。     

ERRγ在子宫内膜癌组织中的表达及临床意义

目的：探讨雌激素受体相关受体γ（estrogen receptor-related receptorsγ,ERRγ）在子宫内膜癌组织中的表达及其临床意义。方法：采用免疫组织化学链霉菌抗生物素蛋白过氧化物酶（SP）法检测40例子宫内膜癌组织及20例正常子宫内膜组织ERRγ和ERα蛋白的表达。采用Real-time PCR方法检测40例子宫内膜癌组织ERRγmRNA的表达水平,分析其与临床病理特征的关系。结果：ERRγmRNA和蛋白的表达在子宫内膜癌组织中均高于正常子宫内膜组织,差异有统计学意义（P〈0.05）;ERRγmRNA在子宫内膜癌中的表达与各临床病理特征之间无关（P〉0.05）。然而ERRγmRNA在ERα阳性的子宫内膜癌中的表达水平与肌层浸润程度有关,差异有统计学意义（P〈0.05）。结论：ERRγ子宫内膜癌中呈现高表达,且表达水平与肌层浸润程度有关,提示ERRγ对子宫内膜癌的发生发展起促进作用。     

PTEN、p53在子宫内膜浆液性癌和宫内膜样癌中的表达及临床病理意义

目的研究PTEN和p53在子宫内膜浆液性癌和宫内膜癌中的表达及临床病理意义。方法应用免疫组化方法检测26例宫内膜浆液性癌、42例宫内膜样癌和25例正常增生期宫内膜组织中PTEN、p53蛋白的表达。结果PTEN和p53蛋白在子宫浆液性癌、宫内膜样癌、正常增生期内膜中的阳性表达率分别为86.4%、28.6%、100%和76.9%、27.3%、0%。PTEN在子宫内膜样癌中阳性表达率明显低于浆液性癌(P<0.001)。p53蛋白表达与子宫内膜癌组织学类型、临床分期、病理分级、肌层浸润等因素有关(P<0.05)。结论PTEN突变和表达缺失与宫内膜样癌的发生、发展有关。p53基因突变和过表达与宫内膜浆液性癌发生发展关系密切。PTEN及p53蛋白检测对鉴别子宫浆液性癌与宫内膜样癌有重要价值。     

Clinical implications of expression of ETS-1 related to angiogenesis in uterine endometrial cancers.

BACKGROUND: Angiogenesis is essential for development, growth and advancement of solid tumors. During angiogenesis, ETS-1 is strongly expressed in vascular endothelial cells and the adjacent interstitial cells, while the inhibition of ETS-1 expression leads to suppression of angiogenesis. This prompted us to study the clinical implications of ETS-1 in relation to angiogenesis in uterine endometrial cancers. PATIENTS AND METHODS: Sixty patients underwent resection for uterine endometrial cancers. From the tissues of 60 uterine endometrial cancers, the levels of ets-1 mRNA, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF) and interleukin (IL)-8 were determined by competitive RT-PCR using recombinant RNA and enzyme immunoassay, and the localization and counts of microvessel were determined by immunohistochemistry. RESULTS: There was a significant correlation between microvessel count and ets-1 gene expression levels in uterine endometrial cancers. Immunohistochemical staining revealed that the localization of ETS-1 was similar to that of vascular endothelial cells. The level of ets-1 mRNA tended to increase with increasing disease stage. Furthermore, the level of ets-1 mRNA correlated with levels of VEGF in well-differentiated adenocarcinomas (G1) and of bFGF in moderately differentiated adenocarcinomas (G2) and poorly differentiated adenocarcinomas (G3). CONCLUSIONS: ETS-1 is a possible angiogenic mediator in uterine endometrial cancers.     

MTA1表达与子宫内膜癌相关性研究

  目的  研究转移相关基因1(metastasis-assoeiatid-genel, MTA1)表达水平与子宫内膜癌发生发展的关系。  方法  采用免疫组织化学SP法检测449例子宫内膜组织中MTA1的蛋白表达水平, 其中正常子宫内膜组织100例, 不典型增生子宫内膜组织49例, 子宫内膜癌组织300例, χ2检验分析比较3组MTA1表达水平差异, 分析MTA1蛋白表达水平与子宫内膜癌分化程度、临床分期、肌层浸润深度的关系。  结果  MTA1蛋白在正常子宫内膜、不典型增生子宫内膜及子宫内膜癌组织中的表达水平存在显著性差异, 在癌组织中呈现显著的过表达, 且与子宫内膜癌不同的组织学分级呈负相关, 与不同的肌层浸润深度及临床分期呈正相关, 且组间差异有统计学意义(P < 0.05)。  结论  MTA1表达水平的增高与子宫内膜癌的发生、分化程度、临床分期及肌层浸润深度密切相关, 可能在其发生发展过程中发挥着重要作用, 通过进一步研究确定其能否成为预测子宫内膜癌发生及浸润转移的有效生物学标志, 为子宫内膜癌的诊断及治疗提供依据。      

高迁移率族蛋白A2在子宫内膜癌中的表达及意义

目的：探讨高迁移率族蛋白A2（high mobility group proteinA2,HMGA2）在子宫内膜癌细胞系AN3CA、ECC-1、Ishikawa以及子宫内膜癌组织、正常子宫内膜组织中的表达及意义。方法：采用逆转录-多聚合酶链反应（RT—PCR）、免疫印迹法（Western Blot）检测HMGA2在体外培养的子宫内膜癌细胞系AN3CA、ECC-1、Ishikawa以及21例子宫内膜癌组织标本和18例正常子宫内膜组织标本中的表达。结果：HMGA2-mRNA在子宫内膜癌细胞系AN3CA、ECC-1、Ishikawa中均有表达;在Ⅰ期、Ⅱ期子宫内膜癌患者中表达的阳性率分别为8．3％（1／12）、88．9％（8／9）,HMGA2-mRNA表达的阳性率与手术-病理分期有关（P=0．000,P〈0．05）,在高分化腺癌、中低分化腺癌的组织标本中表达阳性率分别为66．7％（4／6）、33．3％（5／15）,HMGA2-mRNA表达阳性率与子宫内膜癌细胞的分化程度无关（P=0．331,P〉0．05）;HMGA2-mRNA在18例正常子宫内膜组织标本中无一例表达;Western Blot的结果与RT—PCR的结果相符合。结论：HMGA2基因可能参与了子宫内膜癌的发生和发展,在子宫内膜癌细胞的增殖与侵袭中可能发挥重要作用。     

ezrin和flt-1在子宫内膜癌中的表达及其意义

目的探讨膜细胞骨架连接蛋白ezrin、血管内皮生长因子受体1（flt-1）在子宫内膜癌中的表达及其与临床病理参数之间的关系.方法采用免疫组化方法检测79例子宫内膜癌和12例转移灶组织中ezrin和flt-1蛋白的表达,选择不典型增生14例,单纯、复合性增生20例和正常子宫内膜增生期15例作为对照.结果 ezrin蛋白在正常内膜,单纯、复合性增生, 不典型增生和内膜癌四组间的差异有显著性（P＜0.01）,不典型增生组ezrin的表达高于单纯、复合性增生,内膜癌高于不典型增生.多数正常和增生腺上皮细胞不表达ezrin,而大多数不典型增生和内膜癌细胞表达ezrin,且为细胞浆和细胞膜弥散着色,差异有显著性.内膜癌中,深肌层浸润组ezrin的表达高于浅肌层或无肌层浸润组（P＜0.05）.flt-1在不典型增生中的表达高于正常内膜,内膜癌中flt-1的表达强度随组织学分级升高而降低（P＜0.05）.内膜癌中ezrin与flt-1的表达间无明显相关性,ezrin与雌激素受体（ER）间存在负相关.结论 ezrin可能参与了子宫内膜癌的发生和演进过程.