Megestrol acetate drives endometrial carcinoma cell senescence via interacting with progesterone receptor B/FOXO1 axis

Megestrol acetate is a common and efficient anticancer progesterone. To explore the activity and the therapeutic mechanisms of megestrol acetate in endometrial cancer, human endometrial cancer cell lines Ishikawa and HHUA overexpressing progesterone receptor A (PR-A) and progesterone receptor B (PR-B) were treated with megestrol acetate. Cell viability, apoptosis, cycle arrest, and senescence, as well as the expressions of p21 and p16, two hallmarks of cellular senescence, were evaluated. Compared with the control, >10 nmol/L megestrol acetate treatment could significantly reduce endometrial cancer cell growth, and induce the irreversible G1 arrest and cell senescence. The expression of cyclin D1 in megestrol acetate treated cells was downregulated, while the expressions of p21 and p16 were upregulated via PR-B isoform. FOXO1 inhibitor AS1842856 could significantly abrogate megestrol acetate-induced cell senescence, suggesting that FOXO1 was involved in megestrol acetate/PR-B axis. These findings may provide a new understanding for the treatment of human endometrial cancer.     

Prognostic significance of BAF57 expression in patients with endometrial carcinoma

This study was conducted to elucidate the prognostic significance of BAF57 in patients with endometrial carcinoma. We investigated the relationship between the immunohistochemical expression of BAF57 and various clinicopathological variables in 111 endometrial carcinomas. Both univariate and multivariate regression analyses were performed. The correlations between the BAF57 expression and the other variables including estrogen receptor (ER) and p53 were examined. The high nuclear BAF57 expression was detected in 42 (37.8%) endometrial carcinomas, and 69 (62.2%) endometrial carcinomas were defined as having low nuclear BAF57 expression. The BAF57 expression was significantly associated with the surgical stage, grade of the tumor, myometrial invasion, lympho-vascular space invasion (LVSI) and lymph node metastasis. The 10-year overall survival rates of patients with low and high BAF57 expression were 96.9% and 58.2%, respectively (p<0.001). A multivariate analysis identified BAF57 expression as an independent prognostic factor. The BAF57 expression was significantly correlated with p53 expression (r=0.312, P=0.001), but was not correlated with ER expression (r= -0.141, P=0.14). The high BAF57 expression is an independent marker of poor prognosis of the patients in endometrial carcinomas. The inhibition of BAF57 activity may be one of the candidates for endometrial cancer therapy, especially therapy for aggressive tumors showing overexpression of p53.     

Dominant expression of progesterone receptor form B mRNA in ovarian endometriosis

This study was designed to examine the biological implications of progesterone receptor form A (PR-A) and B (PR-B) mRNA expressions in human ovarian endometriosis (ectopic endometrium). A high ratio of PR-B to PR-AB (PR-A+PR-B) mRNA expression was found in 8 of 14 cases of endometriosis, compared with the ratio in eutopic endometrium. The mean ratio in ectopic endometria was significantly (p < 0.01) higher than in eutopic endometria. The ratio in eutopic and ectopic endometria showed no significant change during the menstrual cycle. The mean ratio in ectopic endometria in the proliferative and secretory phases of the endometrium was significantly (p < 0.01) higher than in eutopic endometria. In conclusion, PR-B mRNA was relatively highly expressed in some endometriomas, which might lead to aberrations in the control of progestational effects involving responsiveness to sex steroidal growth regulation.     

PTEN基因和P53基因在子宫内膜癌中的表达及意义

目的:探讨PTEN基因和P53基因在子宫内膜癌中的表达及临床意义,为子宫内膜癌的治疗提供参考依据。方法:用免疫组化法检测50例子宫内膜癌患者PTEN基因缺失和P53基因突变情况,并分析两者与子宫内膜癌不同病理变化的相关性。结果:PTEN缺失24例,缺失率48.00%,进一步研究显示PTEN缺失与细胞分化程度和肌层浸润情况密切相关(P0.05),P53突变32例,缺失率64.00%,并进一步研究显示P53突变与FIGO分期,细胞分化程度和肌层浸润情况密切相关(P0.05)。结论:PTEN基因缺失和P53基因突变与子宫内膜癌发生和发展密切相关,以PTEN基因和P53基因为靶点的生物治疗在进展期内膜癌中的治疗价值值得进一步深入研究。     

Differential expression of uterine progesterone receptor forms A and B during the menstrual cycle

Recent studies suggest that the progesterone receptor isoforms (PR-A and PR-B) activate genes differentially and that PR-A may act as a repressor of PR-B function. Hence, the absolute and relative expression of the two isoforms will determine the response to progesterone. We have measured their relative expression in the uterus of cycling women who underwent endometrial biopsy. PR isoforms were identified on blots of SDS-PAGE gels by reaction with the AB-52 antibody after immunoprecipitation from endometrial extract. Both isoforms were highest in the peri-ovulatory phase, but levels of PR-A were always higher than those of PR-B. The ratio of PR-A to PR-B changed during the menstrual cycle. Between days 2 and 8, PR-B is almost undetectable and the A:B ratio is >10:1. From days 9 to 13, the ratio is about 5:1, and it is about 2:1 between days 14 and 16. Thereafter, PR-B dwindles rapidly and is virtually undetectable at the end of the cycle. In various hypoestrogenic environments, PR-B expression was reduced. However, exogenous estrogens in the follicular phase in the form of oral contraceptives, enhanced PR-B expression. These data support the possibility that progesterone acts through cycle-specific PR isoforms.     

Ⅰ型子宫内膜癌组织中HIF-1α、Snail与E-cadherin的表达及临床意义

目的探讨I型子宫内膜癌组织中HIF-1α的表达,以及调控Snail和E-cadherin对肿瘤侵袭性生物学行为的影响。方法采用免疫组化方法,结合组织芯片技术,检测124例I型子宫内膜癌、28例内膜不典型增生、35例正常内膜组织中HIF-1α、Snail和E-cadherin的表达水平,分析三种蛋白表达之间的相关性及与临床病理因素的关系。结果 I型子宫内膜癌组织中HIF-1α、Snail和E-cadherin的表达率分别为61.3%、46.8%、36.3%,与正常内膜和不典型增生内膜组织相比,有显著统计学差异(P<0.01)。HIF-1α表达与病理分级、肿瘤肌层浸润和淋巴结转移明显相关(P<0.05)。Snail表达与FIGO分期、淋巴结转移明显相关(P<0.05)。E-cadherin的缺失与肿瘤肌层浸润和淋巴结转移显著相关(P<0.01)。I型子宫内膜癌组织中HIF-1α和Snail的表达呈明显正相关(r=0.214,P=0.017),而Snail和E-cadherin的表达存在负相关关系(r=–0.203,P=0.024)。结论 HIF-1α可能通过上调Snail的表达和抑制E-cadherin的表达在I型子宫内膜癌发生、侵袭和转移中发挥重要作用。     

结直肠癌组织RSK4、p53蛋白的表达及临床病理意义

目的:探讨结直肠癌组织中P90核糖体S6激酶4(RSK4)蛋白、p53蛋白的表达及其临床病理意义。方法:选取我院病理科2014年1月~2016年5月既往收集的结直肠癌手术后标本70例及同期结直肠癌癌旁组织30例,采用免疫组化染色检测两组标本中RSK4蛋白、p53蛋白的表达情况,并分析其与结肠癌患者临床病理特征的相关性。结果:结直肠癌组织中RSK4蛋白、p53蛋白的阳性表达率分别为20.00%、55.71%,而癌旁组织中RSK4蛋白、p53蛋白阳性表达率分别为53.33%、10.00%,两组比较差异均具有统计学意义(P0.05)。Ⅰ期+Ⅱ期、高分化和中分化结直肠癌组织RSK4蛋白的阳性表达率显著高于Ⅲ期、低分化结直肠癌(P0.05);Ⅰ期+Ⅱ期、浸润深度(T1、T2)、未发生淋巴结转移的结直肠癌组织中p53蛋白阳性表达率显著的低于Ⅲ期、浸润深度(T3、T4)、发生淋巴结转移的结肠癌组织(P0.05)。结论:结直肠癌组织中RSK4蛋白表达下调、p53蛋白表达上调,二者可能与结直肠癌的发生和发展有关,并可能作为结肠癌诊断和预后评估的参考指标。     

PTEN基因和P53基因在子宫内膜癌中的表达及意义

目的：探讨PTEN基因和P53基因在子宫内膜癌中的表达及临床意义,为子宫内膜癌的治疗提供参考依据。方法：用免疫组化法检测50例子宫内膜癌患者PTEN基因缺失和P53基因突变情况,并分析两者与子宫内膜癌不同病理变化的相关性。结果：PTEN缺失24例,缺失率48.00%,进一步研究显示PTEN缺失与细胞分化程度和肌层浸润情况密切相关（P〈0.05）,P53突变32例,缺失率64.00%,并进一步研究显示P53突变与FIGO分期,细胞分化程度和肌层浸润情况密切相关（P〈0.05）。结论：PTEN基因缺失和P53基因突变与子宫内膜癌发生和发展密切相关,以PTEN基因和P53基因为靶点的生物治疗在进展期内膜癌中的治疗价值值得进一步深入研究。     

Effects of tamoxifen on the endometrium and its mechanism of carcinogenicity

This study was conducted to clarify the clinicopathological characteristics of tamoxifen-associated endometrial carcinomas and its mechanisms of carcinogenesis. Seven patients with tamoxifen-associated endometrial carcinomas (TAM group) and 28 with sporadic endometrioid adenocarcinomas (EMC group) were included in the study. The clinicopathological factors, such as FIGO stage, histological type, grade, lymph node metastases, vascular invasion and the coexistence of hyperplasia, were investigated in both groups. The protein expression of p53, PTEN, hMLH1 and hMSH2 was investigated by immunohistochemistry. Microsatellite instability (MSI), k-ras and p53 mutation were also examined. In the TAM group, the histological types included five endometrioid, one endometrioid combined with serous and one clear cell type. The rates of coexistence with hyperplasia (five of seven cases) and vascular invasion (four cases) were significantly higher in the TAM group. The rates of stage III/IV (four cases) and lymph node metastasis (three cases) tended to be higher in the TAM group. Although there were no significant differences in PTEN, hMLH1 and hMSH2 expression between the two groups, p53 mutation was more frequent in three out of five cases (60%) in the TAM group compared with 2 of 15 cases in the EMC group (13.3%). No significant differences were observed concerning MSI and k-ras mutation in either group. These results suggested that TAM-associated endometrial carcinomas have overlapping biological characteristics of type I and type II endometrial carcinomas. This might explain the somewhat worse prognosis of these tumors than sporadic endometrioid carcinomas.     

Prognostic significance of G6PD expression and localization in lung adenocarcinoma

Abnormal expressions of extracellular matrix (ECM) proteins are correlated with increased tumor progression, an advanced histologic grade, and metastasis. LCN1 cells derived from a pulmonary large cell neuroendocrine carcinoma were grown to form an Aegagropila-shaped conglomeration on a suspension culture dish (LCN1-sus). In contrast, LCN1 cells cultured in a type I collagen dish were adherent and tended to grow as spindle-shaped individual cells (LCN1-co). In this study, aiming at the discovery of predictive markers for tumor invasion, we performed protein profiling between LCN1-sus and LCN1-co cells using two-dimensional gel electrophoresis. Twenty-six protein spots with >1.2-fold quantitative differences between LCN1-sus and LCN1-co cells were detected. Among the identified proteins, we focused on and immunohistochemically investigated G6PD in lung cancer. G6PD expression was significantly associated with a higher pathological TNM stage (p = 0.0024), lymph node metastasis (p = 0.0187), poorer differentiation (p = 0.0046), pleural invasion (p = 0.0197), vascular invasion (p < 0.0001), lymphatic invasion (p = 0.0200) and poorer prognosis (p = 0.0005) in adenocarcinoma. Especially, G6PD-positive patients with overexpression at the invasive front had significantly poorer survival than those without overexpression (p = 0.0058). Moreover, multivariable analysis revealed that G6PD expression was an independent adverse-prognostic factor. These results suggest that G6PD may be a novel predictive prognostic marker for lung adenocarcinoma.     

Claudin-7和β-catenin在正常、增生和恶性子宫内膜组织中的表达和意义

目的恶性肿瘤转移过程与细胞间粘附作用的丧失密切相关。本研究旨在探讨细胞间粘附分子claudin-7和β-catenin在正常、增生和恶性子宫内膜组织中的表达及其在子宫内膜癌中的临床病理意义。方法应用免疫组化检测30例正常增生期子宫内膜、27例非典型增生子宫内膜和43例子宫内膜癌组织中claudin-7和β-catenin的表达情况,统计分析它们与子宫内膜癌病理分级、临床分期、浸润深度及淋巴结转移等指标之间的关系,并对二者表达之间的关系进行探讨。结果在正常增生期子宫内膜、非典型增生子宫内膜和子宫内膜癌中,claudin-7的表达依次减低,阳性率分别为96.7%,66.7%和39.5%,三组之间具有显著差异（P〈0.05）;β-catenin在非典型增生子宫内膜和子宫内膜癌组织中的异位表达率分别为40.7%和74.4%,均显著高于正常增生期子宫内膜（3.3%）（P〈0.01）,子宫内膜癌组织中β-catenin的异位表达率显著高于非典型增生子宫内膜（P〈0.01）。在子宫内膜癌中,claudin-7的表达与临床分期、浸润深度和淋巴结转移有关（P〈0.01）;β-catenin的异位表达与病理分级、临床分期、浸润深度和淋巴结转移有关（P〈0.01）;Claudin-7的表达和β-catenin的异位表达呈显著负相关（r=-0.813,P〈0.01）。结论Claudin-7和β-catenin的异常表达与子宫内膜癌的发生发展有关,并且在此过程中claudin-7逐渐缺失以及β-catenin的异位表达可能对肿瘤的侵袭和转移产生一定作用。     

Expression of progesterone receptor isoforms A and B is differentially regulated by estrogen in different breast cancer cell lines

Progesterone action in target tissues is mediated through two progesterone receptor (PR) isoforms, PR-A and PR-B, which display different regulatory functions in target cells. Relative expression ratio of these isoforms varies depending on cell and tissue types. Here, we studied the regulation of PR isoform expression by estradiol (E(2)), insulin, IGF-1 and cAMP in different breast cancer cell lines. Although, E(2) induced PR expression in all cell lines studied, the expression ratio of PR-A/PR-B induced by E(2) was dependent on the cell line. The differential regulation of the isoforms was also seen at the mRNA level suggesting that the PR-A and PR-B promoters are differentially regulated by E(2) in different breast cancer cells. Insulin, IGF-1 or cAMP previously reported to induce PR expression however failed to alter the PR expression in our study. This is the first report describing that in different breast cancer cell lines the expression of PR-A and PR-B is regulated by E(2) in a distinct way.     

子宫内膜癌组织中uPA及Cath-D的表达及意义(英文)

目的:检测子宫内膜癌组织中尿激酶型纤溶酶原激活物(uPA)及组织蛋白酶(Cath-D)的表达并探讨相关性及其临床意义。方法:采用免疫组织化学方法(PV-6000二步法)检测31例子宫内膜癌组织(内膜癌组),17例子宫内膜增生组织(增生组)及10例正常子宫内膜组织(对照组)中uPA及Cath-D的表达,并研究其相关性。结果:1.内膜癌组中uPA和Cath-D的表达均高于增生组及对照组中的表达,差异均有统计学意义(P0.05);在增生组中的表达与对照组差异无统计学意义(P0.05)。2.uPA和Cath-D的阳性表达与子宫内膜癌的临床病理分期、组织学分级及肌层浸润深度有关,差异均具有统计学意义(P0.05)。3.内膜癌组中uPA与Cath-D的表达呈正相关(r=0.673,P0.05)。结论:uPA和Cath-D在子宫内膜癌发生发展及侵袭转移过程中起着协同作用,Cath-D可诱导产生活化的uPA,促进癌细胞的浸润转移,因此,两者的联合检测可有助于成为判断子宫内膜癌的发展及预后的重要指标。     

Human umbilical vascular endothelial cells express estrogen receptor beta (ERβ) and progesterone receptor A (PR-A), but not ERα and PR-B

Several reports deal with possible effects of female sex hormones on human umbilical vein endothelial cells (HUVEC) including elasticity, activation of plasma membrane Na(+)/H(+) exchange, VEGF receptor Flk-1/KDR and many others. In contrast to those findings, some publications pointed out that HUVEC lack expression of both the estrogen receptor (ER) and/or the progesterone receptor (PR). Because the majority of these investigations were carried out at a time period, when only one ER and one PR was known, the aim of this study was the systematic analysis of ERalpha and ERbeta as well as PR-A and PR-B expression in HUVEC with specific monoclonal antibodies by immunocytochemistry and quantitative RT-PCR (TaqMan). As a result, we could show that HUVEC lack ERalpha but express ERbeta. The expression of ERbeta could be significantly upregulated with 17beta-estradiol on mRNA and protein level. In addition, HUVEC express PR-A but not PR-B. PR-A expression could be significantly upregulated with progesterone, again on mRNA and protein level. We conclude that estrogenic effects on HUVEC are mediated via the ERbeta and gestagens act via the PR-A pathway.