Overexpression of p27kip1 in urinary bladder urothelial carcinoma

OBJECTIVES: Cyclins and cyclin-dependent kinase (CDK) complexes have important regulatory roles during cell cycle progression and can be used as prognostic markers in various kinds of malignant tumors. This study investigated the expression of proliferative cell nuclear antigen (PCNA), p53, Rb, p27(kip1), and cyclin D1 by immunostains in bladder tumors, especially urothelial papilloma, papillary urothelial neoplasm of low malignant potential, and low and high grade urothelial carcinoma, to see if their expression is associated with classification or grading of the urinary bladder urothelial carcinoma. METHOD: Nuclear expression of PCNA, p53, Rb, p27(kip1), and cyclin D1 was determined immunohistochemically in a series of 89 urinary bladder tumor specimens, including 13 papilloma, 15 urothelial neoplasm of low malignant potential, 17 low grade urothelial carcinoma, and 44 high grade urothelial carcinoma. The results of immunoreactivity were analyzed with respect to the associations with tumor grade. RESULTS: Eighty-two percent (38/45) of the p27(kip1) positive tumors were urothelial carcinoma, and the percentage of the p27(kip1) positivity was higher with increasing grade of the urothelial carcinoma (P = 0.011). A tendency of higher percentage of positive p53 immunoreactivity was noted in the urothelial carcinoma (P = 0.053). There was no significant difference in cyclinD1, Rb and PCNA expression between benign, low malignant potential and urothelial carcinoma. CONCLUSION: We first noted an overexpression of p27(kip1) in urinary bladder urothelial carcinoma. The result indicates that some urothelial carcinomas may tolerate this inhibitor of cell cycle progression.     

Expression patterns of cyclins D1, E and cyclin-dependent kinase inhibitors p21(Waf1/Cip1) and p27(Kip1) in urothelial carcinoma: correlation with other cell-cycle-related proteins (Rb, p53, Ki-67 and PCNA) and clinicopathological features

INTRODUCTION: The expression pattern of cyclins D1 and E, as well as cyclin-dependent kinase inhibitors p21(Wa1/Cip1) and p27(Kip1) and their relationship to tumour behaviour and patients' prognosis was examined in 142 urothelial cell carcinomas. The expression of these proteins was also analyzed along with other cell-cycle-related proteins such as: p53, pRb and the proliferation-associated indices Ki-67 and proliferating cell nuclear antigen (PCNA). PATIENTS AND METHODS: These molecule markers were localized immunochemically using the monoclonal antibodies anti-cyclin D1 (DCS-6), anti-cyclin E (13A3), anti-p21 (4D10), and anti-p27 (1B4) in 142 patients with urothelial cell carcinoma. RESULTS: Focal positivity (<10% of tumour cells) or the absence of cyclin D1 immunostaining was observed in 105/142 (73.9%) of the tumours. Cyclin D1 expression was correlated with tumour grade and stage as well as with the existence of in situ component. In addition, cyclin D1 expression was positively correlated with p21(Waf1/Cip1) and p27(Kip1) and inversely with the Ki-67 score. Focal positivity (<20% of tumour cells) or the absence of cyclin E immunoreactivity was observed in 105/142 (73.9%) in all cases. Cyclin E expression was correlated with tumour stage. A positive relationship between cyclin E expression and the two associated proliferating indices Ki-67 and PCNA, as well as with p53 and p27(Kip1) proteins expression was noted. Absence or focal positivity (<5% of tumour cells) of p21(Waf1/Cip1) was detected in 88/142 (62%) of the carcinomas. p21(Waf1/Cip1) expression was correlated with tumour grade and stage. A positive relationship of its expression cyclin D1, cyclin E, p27 and pRb expression was observed. Absence or focal immunostaining (<20% of tumour cells) of p27 protein was detected in 55/141 (39%) in all cases. p27(Kip1) expression was correlated with tumour grade as well as with cyclins D1 and E. The prognostic significance of cyclins D1, E and cyclin-dependent kinase inhibitors p21(Waf1/Cip1), p27(Kip1) in determining the risk of recurrence and progression with both univariate (log rank test) and multivariate (Cox regression) methods of analysis showed no statistically significance differences. CONCLUSION: These findings suggest that the level of the cell cycle regulators studied does not seem to have a clinical value in terms of predicting the risk of early recurrence and progression. In addition the interrelationship probably means their contribution to the regulation of cell growth through different pathways in bladder carcinogenesis.     

胃癌中cyclin D1、cyclin E和p27的表达及其意义

目的 探讨cyclinD1、cyclinE和p27蛋白在胃癌中的表达及其意义。用免疫组化法检测60例胃癌组织中cyclinD1,Cyclin E和p27蛋白的表达。结果 胃癌组织中cyclinD1,cyclinE和p27蛋白表达阳性率分别为41．7％（25／60）、38．3％（23／60）和36．7％（22／60）;cyclinD1在胃癌中的表达与肿瘤Lauren分型相关,cyclinE在胃癌中的表达与肿瘤分化程度、浸润深度及肿瘤分期相关,而p27蛋白的表达与肿瘤浸润深度、淋巴结转移和肿瘤分期相关。另外,cyclinE和p27蛋白 在胃癌中的表达呈显著负相关。结论 检测胃癌细胞中cyclinD1,cyclinE和p27蛋白的表达有助于判断肿瘤的进展程度。     

Expression of cyclooxygenase-2 in normal urothelium, and superficial and advanced transitional cell carcinoma of bladder

PURPOSE: We compared the differential expression of cyclooxygenase-2 in normal bladder tissue, primary bladder transitional cell carcinoma and transitional cell carcinoma metastases to lymph nodes, and determined whether cyclooxygenase-2 expression is associated with molecular alterations commonly found in bladder transitional cell carcinoma and clinical outcomes after radical cystectomy. MATERIALS AND METHODS: Immunohistochemical staining for cyclooxygenase-2, survivin (Novus Biologicals, Littleton, Colorado), p21, p27, pRB, p53, MIB-1, Bax, Bcl-2, cyclin D(1) (Dakotrade mark), cyclin E (Oncogene, Cambridge, Massachusetts) and caspase-3 (Cell Signaling, Beverley, Massachusetts) was performed on archival bladder specimens from 9 subjects who underwent cystectomy for benign causes, 21 patients who underwent transurethral resection and 157 consecutive patients after radical cystectomy, and on 41 positive lymph nodes. RESULTS: Cyclooxygenase-2 was expressed in none of the 9 normal bladder specimens (0%), 52% of transurethral resection specimens, 62% of cystectomy specimens and 80% of lymph nodes involved with transitional cell carcinoma. Cyclooxygenase-2 expression was associated with higher pathological stage, lymphovascular invasion and metastases to lymph nodes (p=0.001, 0.045 and 0.002, respectively). Cyclooxygenase-2 expression was associated with altered expression of p53 (p=0.039), pRB (p=0.025), cyclin D1 (p=0.034) and caspase-3 (p=0.014). On univariate analysis cyclooxygenase-2 expression was associated with an increased risk of disease recurrence and bladder cancer specific mortality (p=0.0189 and 0.0472, respectively). However, on multivariate analysis only pathological stage and metastases to lymph nodes were associated with disease recurrence (p<0.001 and <0.001) and survival (p<0.001 and 0.015, respectively). CONCLUSIONS: Cyclooxygenase-2 is not expressed in normal bladder urothelium. Cyclooxygenase-2 over expression is associated with pathological and molecular features of biologically aggressive disease, suggesting a role for cyclooxygenase-2 in bladder cancer development and invasion.     

细胞周期蛋白D1在膀胱移行细胞癌中表达的意义

目的　探讨细胞周期蛋白Ｄ１（ｃｙｃｌｉｎ Ｄ１） 与膀胱移行细胞癌（ＴＣＣ） 生物学行为的关系。　方法　应用免疫组化法检测７１ 例膀胱ＴＣＣ 组织中ｃｙｃｌｉｎ Ｄ１ 的表达。　结果　３９ 例（５４ ．９％ ）ＴＣＣ 中ｃｙｃｌｉｎ Ｄ１ 呈阳性表达,其中Ｇ１ １１ 例（６８－８ ％ ）、Ｇ２ ２３ 例（６０－５ ％ ）、Ｇ３ ５ 例（２９－４ ％ ） 。３２ 例为胞核阳性,７ 例为胞浆阳性,其中Ｇ２ ３ 例,Ｇ３ ４ 例。６０ 例初发者阳性３５ 例（５８－３ ％ ） ,１１ 例再发者阳性４ 例（３６－４％ ） 。　结论　膀胱ＴＣＣ 是ｃｙｃｌｉｎ Ｄ１ 高表达的肿瘤类型之一,ｃｙｃｌｉｎ Ｄ１ 的过表达是膀胱癌发生过程中的早期事件,其与肿瘤病理分级显著相关,再发性ＴＣＣ 中表达有减少趋势,胞浆阳性代表着更高的恶性潜能     

金属硫蛋白1E对胰腺癌SW1990细胞生长的影响

目的 观察外源性人金属硫蛋白1E(MT1E)基因对胰腺癌SW1990细胞生长的影响.方法 构建MT1E基因真核表达载体,转染SW1990细胞并获得阳性单克隆细胞.用Westernblot技术检测转染前后MT1E蛋白表达,噻唑蓝(MTT)实验检测其增殖能力的变化,流式细胞仪分析细胞周期时相分布.同时检测Cyclin D1与p53的表达.结果 MT1E融合蛋白在SW1990MT1E细胞中表达.MTT结果表明,与SW1990和SW1990MT1E空细胞比较,SW1990MT1E细胞增殖速度明显增快.SW1990MT1E细胞与SW1990和SW1990空细胞比较,G0/G1期细胞明显减少,S期明显增多,差异有统计学意义.SW1990MT1E较SW1990空的细胞Cyclin D1与p53表达明显升高.结论 MT1E能够促进SW1990增殖,可能和上调Cyclin D1促使细胞进入S期增多,通过失活p53蛋白使细胞恶性变.     

Cyclin D1、p27、ki-67在膀胱移行细胞癌中的表达及其意义

目的探讨Cyclin D1、p27、ki-67在膀胱移行细胞癌（BTCC）中的表达及其临床意义。方法采用免疫组化SP法检测72例BTCC和8例正常膀胱黏膜组织中Cyclin D1、p27、ki-67的表达。结果CyclinD1及ki-67在BTCC中的表达明显高于正常对照，而p27的表达低于正常对照，且均与膀胱肿瘤的分级分期相关。结论Cyelin D1、p27、ki-67的表达可能与BTCC的生物学行为有关。     

STAT3和Cyclin D1在人脑胶质瘤中的表达及其意义

目的 探讨信号转导及转录激活因子3(STAT3)和细胞周期蛋白D1(Cyclin D1)表达与脑胶质瘤生物学行为的关系及意义.方法 用逆转录-聚合酶链反应(RT-PCR)和Western blot方法检测并比较68例不同级别胶质瘤和10例正常脑组织中STAT3和Cyclin D1的表达,并对两者表达做相关分析.结果 RT-PCR检测胶质瘤组织STAT3、Cyclin D1的mRNA表达量(2.23±0.32、2.18±0.26)均明显高于正常脑组织(0.53±0.14、0.48±0.11),Western blot检测胶质瘤组织STAT3、Cyclin D1的蛋白表达量(42.3±2.6)%、(45.4±1.8)%均明显高于正常脑组织(9.8±1.1)%、(10.4±0.9)%,其差异均有统计学意义(P＜0.05),STAT3和Cyclin D1的表达与胶质瘤级别呈正相关.结论 STAT3可能通过激活其下游靶基因Cyclin D1,引起胶质瘤细胞异常增殖和分化失控.     

Pin1和周期素D1在胰腺癌中的表达及其意义

目的:检测胰腺癌及癌旁组织中Pin1和周期素D1基因的表达,探讨Pin1在胰腺癌发病中所起的作用。方法:收集27例胰腺肿瘤组织及其相应的肿瘤旁组织标本,采用实时荧光定量逆转录聚合酶链反应法（RQ RT-PCR）检测胰腺良恶性肿瘤及肿瘤旁组织中Pin1和周期素D1 mRNA 的表达,运用Fisher精确概率分析两者之间的相关性及其与肿瘤临床分期和病理特征的关系。结果:7例胰腺囊腺瘤中周期素D1和Pin1的表达与肿瘤旁组织之间无显著性差异;而20例胰腺癌中周期素D1和Pin1的表达明显高于肿瘤旁组织［（2.78±1.02）vs.（4.36±1.27）和(5.48±1.69) vs. (9.97±1.86),P<0.05）］。Pin1和周期素D1与肿瘤的临床分期和病理分化程度无明显的相关（组间差异均为P>0.05）,但Pin1与周期素D1的表达有关（P<0.01）。 结论:胰腺癌中Pin1的过表达可促进周期素D1表达,由此诱导了肿瘤的发生;Pin1可能在胰腺癌中起着重要作用。     

细胞周期蛋白E和p27kip1在膀胱癌中的表达及意义

目的　探讨细胞周期蛋白E(cyclinE)和p2 7kip1在膀胱移行细胞癌中的表达及临床意义。　方法　采用免疫组化SP法观察 69例膀胱癌石蜡标本中cyclinE和 p2 7kip1的表达情况 ,结合临床资料进行分析。　结果　膀胱癌组织中cyclinE和 p2 7kip1阳性表达率分别为 42 %和 51 %。cy clinE阳性表达率在复发肿瘤中及随病理分级升高而升高 (P <0 .0 5) ,但与临床分期无关 (P >0 .0 5) ;p2 7kip1阳性表达率随病理分级、临床分期升高及在复发肿瘤中下降 (P <0 .0 1 )。cyclinE与 p2 7kip1二者的阳性表达有显著相关性 (P <0 .0 1 )。　结论　cyclinE和p2 7kip1表达可能是判断膀胱癌生物学行为的重要指标     

DMBA诱导大鼠乳腺癌与纤维肉瘤中cyclin D1及p53蛋白的表达及其意义

目的 探讨cyclinD1和p53蛋白在实验性大鼠同时性乳腺癌与纤维肉瘤中的表达及其意义。方法 通过改良给药的方法复制大鼠同时性乳腺癌与纤维肉瘤动物模型,应用SP免疫组化技术检测cyclinD1和p53蛋白在乳腺癌、纤维肉瘤及瘤旁组织中的表达。结果 在正常乳腺组织中无 D1和p53蛋白表达,在不典型增生乳腺组织中7／14有cyclinD1表达,8／18的乳腺癌与9／14的纤维肉瘤中有cyclin D1的表达,7／18的乳腺癌与5／14的纤维肉瘤中有p53蛋白的过度表达;肉瘤旁组织无cyclinD1和p53蛋白表达。cyclinD1和p53蛋白表达与乳腺癌和纤维肉瘤组织学分级有关,同时二者的表达呈负相关。结论 在大鼠同时性乳腺癌与纤维肉瘤中有cyclinD1和p53蛋白过度表达,cyclinD1蛋白可能参与肿瘤发生过程,而p53蛋白表达与肿瘤的恶性程度相关。     

Expression of p16 and cyclin D1 in bladder cancer and correlation in cancer progression

INTRODUCTION: Gene p16 encodes a cyclin-dependent kinase inhibitor which functions to regulate cyclin D1, cell cycle progression and malignancies. The relationship between p16 and cyclin D1 is thought to alter bladder cancer formation and tumor progression. We aimed to investigate the expression of p16 and cyclin D1 genes in order to evaluate their clinical significance in bladder cancer. MATERIALS AND METHODS: Tissue samples from 67 patients with transitional cell carcinoma were examined with an immunohistochemical stain for the expression of p16 and cyclin D1 genes. The expression rate was compared to 12 normal urinary bladder mucosa samples obtained from transurethral surgery from noncancer patients. RESULTS: The results revealed significant differences between normal bladder mucosa (100%) and cancer tissue (40.3%) for the positive staining of p16 protein (p < 0.001), while positive staining for the cyclin D1 protein in the patient group (67.2%) was significantly higher (p = 0.003) than that in the control group (16.7%). With the progression of tumor grade and clinical staging the positive rate of p16 gene expression increased, whereas, that of cyclin D1 decreased. Expression of the p16 gene in the non-invasive group was greater than that in the invasive group and a lower expression rate of the cyclin D1 gene in the non-invasive group compared to the invasive group. CONCLUSIONS: The results revealed that expression of the p16 gene is inversely proportional to the expression of the cyclin D1 gene. Therefore, abnormal expression of the p16 and cyclin D1 genes play important roles in tumorigenesis and tumor progression.     

细胞周期蛋白D1和P21WAF1在胃癌中的表达及其与化疗药物敏感性的关系

目的检测细胞周期蛋白（cyclin）D1、P21WAF1在胃癌组织中的表达,并探讨其与化疗药物敏感性的关系。方法采用MTT比色法观察80例胃癌原代培养细胞在体外对化疗药物羟基喜树碱（HCPT）、顺铂（DDP）、阿霉素（ADM）、氟尿嘧啶（5-Fu）及丝裂霉素（MMC）的敏感性;免疫组织化学染色检测cyclin D1和P21WAF1蛋白在胃癌组织中的表达情况。结果胃癌细胞对不同化疗药物敏感性不同：5-FU、MMC和DDP对胃癌细胞的抑制率显著高于ADM和HCPT（P〈0．05）。胃癌组织中cvclin D1和P21WAF1蛋白的阳性率分别为70．0％和47．5％。cyclin D1阳性表达者对5-Fu和HCPT的敏感性显著高于阴性表达者（P〈0．05）,而P21WAF1阴性表达者对MMC、5-FU和DDP的敏感性显著高于阳性表达者（P〈0．05）。结论cyclin D1和P21WAF1蛋白与胃癌对化疗药物敏感性有关．检测其表达对于化疗药物的选择具有一定的参考价值。     

CyclinD1在肾细胞癌中的表达及其意义

目的探讨细胞周期蛋白D1（CyclinD1）在肾细胞癌中的表达及其意义。方法采用免疫组织化学技术,检测60例。肾细胞癌患者中肾癌组织及癌旁肾组织中CyclinD1的表达,并对Cyclin D1的表达与临床病理参数的关系进行分析。结果CyclinD1在肾细胞癌组织中的阳性率为83．3％,而癌旁肾组织中的阳性率为6．6％,两者具有显著性差异（P〈0．05）。Cyclin D1在肾细胞癌组织中的表达在不同性别、年龄、肿瘤体积组无显著差异（P〉0．05）。结论CyclinD1可作为判断肾细胞癌分化程度的标志物。     

cyclin E和p27kip1蛋白在胆囊癌组织中的表达及其意义

目的　探讨cyclinE和 p2 7kip1蛋白在胆囊癌组织中的表达及其意义。方法　采用免疫组化SP法检测 4 1例胆囊癌和 15例慢性胆囊炎组织中cyclinE及p2 7kip1蛋白的表达 ,并分析两者的表达与胆囊癌临床病理特征的关系。结果　cyclinE在胆囊癌组织中的表达阳性率为 6 1.0 % (2 5 / 4 1) ,显著高于慢性胆囊炎的 2 0 .0 % (3/15 ) ,P<0 .0 5 ;胆囊癌组织中p2 7kip1蛋白的表达阳性率为 5 3.7% ,低于慢性胆囊炎的 10 0 % (P<0 .0 5 )。cyclinE的表达与胆囊癌TNM分期呈正相关 (r =0 .314 ,P<0 .0 5 ) ,p2 7kip1蛋白的表达则随胆囊癌TNM分期进展、组织学分化程度的降低而逐渐下降 (P<0 .0 5 ) ,cyclinE与 p2 7kip1蛋白表达之间呈负相关 (r =- 0 .342 ,P<0 .0 5 )。结论　cyclinE蛋白高表达和 p2 7kip1蛋白表达下降导致细胞周期的调控异常 ,可能参与了胆囊癌的发生、发展过程。     

Cyclin D1 expression is predictive of occult metastases in head and neck cancer patients with clinically negative cervical lymph nodes

BACKGROUND: The aim of this study was to investigate the value of p53 and cyclin D1 gene expression in predicting the risk of occult lymph node metastases in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: The expression of cyclin D1 and p53 was evaluated by means of immunohistochemical analysis in 32 HNSCC patients with clinically and radiologically negative lymph nodes in whom metastatic involvement was subsequently demonstrated at histologic examination (pN+). A group of 64 head and neck cancer patients with histologically negative laterocervical lymph nodes (pN0) was used as a control. RESULTS: Cyclin D1 and p53 expression were observed respectively in 42 (43.7%) and 48 cases (50%). Cyclin D1 expression significantly correlated with tumor extension and advanced clinical stage (p =.002 and p =.001, respectively). At univariate regression analysis, cyclin D1 expression significantly correlated with the presence of occult lymph node metastases (p =. 0007), and it remained an independent predictor at multivariate regression analysis (p =.0059). CONCLUSIONS: Our study indicates that the expression of cyclin D1 correlates with the presence of occult cervical metastases in head and neck carcinoma patients, thus suggesting that its immunohistochemical evaluation in biopsy samples may be used as an additional tool for identifying patients to be treated with elective neck dissection.     

Predictive value of cell cycle biomarkers in nonmuscle invasive bladder transitional cell carcinoma

PURPOSE: We determined whether the combined expression of p53, p21, p27 and pRB is associated with outcomes of patients with nonmuscle invasive bladder transitional cell carcinoma. MATERIALS AND METHODS: Immunohistochemical staining for p53, p21, p27 and pRB was performed on archival bladder specimens from 9 normal controls and 74 patients who underwent transurethral bladder tumor resection for Ta, Tis and/or T1 transitional cell carcinoma. RESULTS: Normal urothelium had wild type status of p53, pRB, p21 and p27. p53 expression was altered in 34% of patients with transitional cell carcinoma, pRB in 39%, p21 in 35% and p27 in 47%. When analyzed separately, p53, pRB and p21 were each independently associated with tumor progression. Combination of biomarkers stratified patients into statistically significantly different risk groups for disease recurrence and progression. When tumor stage and grade were modeled with all 4 biomarkers, p53 and p27 were the sole independent predictors of disease recurrence and progression. After controlling for the effects of tumor grade and stage, the incremental number of altered biomarkers was associated with an increased risk of bladder cancer recurrence (p for trend = 0.011) and progression (p for trend = 0.005). The risk ratio for disease recurrence and progression increased incrementally with the number of biomarkers altered. CONCLUSIONS: Combinations of p53, pRB, p21 and p27 had cooperative/synergistic effects stratifying patients into different risk groups. Higher total numbers of altered biomarkers were independently associated with an increased risk of disease progression and death. Prospective trials are necessary to usher bladder cancer management into the age of molecular biomarkers.     

Association of tumor-associated trypsin inhibitor (TATI) expression with molecular markers, pathologic features and clinical outcomes of urothelial carcinoma of the urinary bladder

Purposes

To describe the differential tissue expression of tumor-associated trypsin inhibitor (TATI) in normal bladder urothelium, primary urothelial carcinoma of the bladder (UCB) and metastatic UCB and to assess the association of TATI expression with molecular markers commonly altered in UCB and clinical outcomes after radical cystectomy.

Methods

Slides from eight cystectomy patients without cancer, 191 radical cystectomy patients, 20 lymph nodes without metastasis and 40 lymph nodes with UCB were stained. Tissue expression of TATI, cyclin E1, cyclin D1, p53, p21, p27, pRB, Ki-67, Bcl-2, Caspase-3, Survivin and Cyclooxigenase-2 was measured in a tissue microarray. Cancer-specific and recurrence-free survival after radical cystectomy was recorded.

Results

TATI was expressed in 100% of patients without cancer, while 71% of radical cystectomy specimens and 90% of lymph node metastases exhibited decreased or no TATI expression. In radical cystectomy specimens, TATI expression decreased with advancing pathologic stage (P?P?=?0.055). In univariate analyses, but not in multivariable Cox proportional hazard regression analyses, decreased TATI expression was associated with increased probability of tumor recurrence and cancer-specific mortality. Decreased TATI expression was correlated with altered expression of Cyclooxigenase-2 (P?=?0.005), p21 (P?=?0.035) and Ki-67 (P?=?0.004).

Conclusions

We found that normal urothelium expresses TATI and that TATI expression decreases with advancing tumor stage. While there was no prognostic benefit to TATI when adjusted for standard clinicopathologic features, it seems to play an important biologic role in UCB pathogenesis and invasion. Its association with markers involved in the cell cycle, proliferation and inflammation serves as hypothesis for molecular interactions.     

Evaluation of p21WAF1/CIP1 and cyclin D1 expression in the progression of superficial bladder cancer

Immunoreactivity of p21^WAF1/CIP1 and cyclin D₁ proteins was assessed in a cohort of 207 patients with superficial (pTa-pT₁) bladder cancer followed up for a mean of 4.9 years. The results of the immunostainings were compared with T category, WHO grade, tumor cell proliferation rate (MIB-1 score), the expressions of p53 and bcl-2 as well as survival. Sixty-eight percent and 75% of the tumors were p21^WAF1/CIP1 positive (≥5% of cells positive) and cyclin D₁ positive (≥10% of cells positive), respectively. The p21^WAF1/CIP1 expression was related to cyclin D₁ immunolabelling (P < 0.001) but not to the other variables studied. The expression of cyclin D₁ was inversely associated with T category (P=0.001), WHO grade (P=0.006), MIB-1 score (P=0.014), p53 expression (P=0.001), and bcl-2 (P=0.011) immunoreactivity. In univariate analysis, T category (P=0.0001), WHO grade (P < 0.0001), MIB-1 score (P < 0.0001), bcl-2 (P=0.0092), p53 (P=0.0016) and p21^WAF1/CIP1 (P=0.009) expressions were significant prognostic factors with regard to tumor progression, whereas cyclin D₁ was without any prognostic significance (P=0.1). Out of 123 p21 positive tumors 21 progressed, whereas only 2 out of 58 p21 negative tumors progressed. In multivariate analysis, the MIB-1 score was the only independent predictor of cancer-specific survival (P=0.03), whereas tumor grade (P=0.002) and cyclin D₁ expression (P=0.04) were independent predictors of tumor recurrence. Only the WHO grade (P=0.04) retained its prognostic value indicating the risk of progression. We suggest that in superficial bladder cancer p21^WAF1/CIP1 and cyclin D₁ immunohistochemistry provide no additional prognostic information compared with already established prognostic factors for predicting the risk of progressive disease. Received: 13 September 1999 / 22 March 2000     

Expression of p27<Superscript>(Kip1)</Superscript>, cyclin D3 and Ki67 in BPH,prostate cancer and hormone-treated prostate cancer cells

p27^(Kip1), cyclin D3 and Ki67 are the markers of DNA damage and cell proliferation. The goal of the current study was to analyze expression of the markers in benign and malignant prostate cancer tissues. Activity of p27^(Kip1), cyclin D3 and Ki67 was immunohistochemically evaluated in different cells of BPH, prostate cancer (PCa) and hormonally treated prostate cancer (HTPCa) tissues. The tissue samples were derived by means of TURP or radical prostatectomy. Intensity of the expression was compared between the groups, and association was sought with clinical parameters. Total expression of p27^(Kip1) was significantly higher in BPH as compared with PCa. Epithelial marker expression was higher in HTPCa than in PCa. Intensity of the expression in epithelial, vascular and ductal cells was negatively associated with the tumor stage and Gleason grades. Total Ki67 activity was positively correlated with patient age and serum PSA level. There was significantly higher expression in PCa and hormone-escaped PCa (HEPCa) as compared with BPH. Epithelial and vascular marker expression was positively associated with tumor stage and Gleason grades. There was a positive correlation between cyclin D3 and serum PSA level. With the increase of Gleason grades, cyclin D3 expression increased significantly. Expression of p27^(Kip1) negatively correlated with Ki67 and cyclin D3, while the latter two markers correlated positively. p27^(Kip1) is down-regulated, whereas Ki67 and cyclin D3 are up-regulated in PCa. Intensity of the markers’ expression is associated with tumor stage and grades. Hormonotherapy of PCa causes activation of p27^(Kip1). HEPCa is characterized by increased Ki67 expression.