Diagnostic Role of Survivin in Urinary Bladder Cancer

Background: Early diagnosis of carcinoma of bladder remains a challenge. Survivin, a member of theinhibitor of apoptosis (IAP) protein family, is frequently activated in bladder carcinoma. The objective of thisstudy was to investigate urinary survivin as a marker for diagnosis of urinary bladder. Materials and Methods:We examined urinary survivin concentration in 28 healthy individuals, 46 positive controls and 117 cases ofhistologically proven TCC prior to transurethral resection, using ELISA, and compared values with findings forurinary cytology. Results: Survivin was found to be significantly higher in the cancer group (P<0.05). A cut offvalue of 17.7 pg/ml was proposed, with an approximate sensitivity of 82.9% and specificity of 81.1% (P<0.0001),whereas urine cytology had a sensitivity of 66.7% and a specificity of 96.0%. Conclusions: Urinary survivin canbe used as a non-invasive diagnostic biomarker for TCC bladder, both for primary and recurrent disease.     

Survivin expression in breast cancer predicts clinical outcome and is associated with HER2, VEGF, urokinase plasminogen activator and PAI-1.

BACKGROUND: Survivin, a novel inhibitor of apoptosis, is one of the most cancer-specific proteins identified to date. In this study we (a) evaluated the association between survivin and HER2, vascular endothelial growth factor (VEGF) and uPA/PAI-1 expression and (b) defined its effect on clinical outcome in a large breast cancer patient cohort. PATIENTS AND METHODS: Survivin expression was measured by ELISA in primary breast cancer tissue extracts from 420 patients with long-term clinical follow-up. RESULTS: Survivin was detected in 378 (90%) of the 420 primary breast cancer cases. Increased survivin levels were significantly associated with high nuclear grade (P < 0.0001), negative hormone receptor status (P = 0.0028), HER2 overexpression (P = 0.0094), VEGF expression (P < 0.0001), high uPA (P = 0.0002) and PAI-1 levels (P = 0.0002). Using the 25th percentile (1.4 ng/mg) as a cut-off point, patients expressing elevated survivin had a significantly worse disease-free survival (DFS: P = 0.0007, RR 1.97) and overall survival (OS: P = 0.0009, RR 2.11) compared with patients expressing lower levels of survivin. In multivariate analysis, this prognostic value of survivin was independent of both traditional and novel clinicopathologic factors for both DFS (P = 0.0076, RR 1.72) and OS (P = 0.0155, RR 1.76). CONCLUSIONS: The independent prognostic relevance of survivin, when combined with previous data from model systems implicating survivin in the inhibition of apoptosis, suggests that survivin may be a suitable target for future therapeutic strategies.     

Survivin在乳腺癌组织中的表达及其临床意义

目的:探讨Survivin在乳腺癌组织中的表达与凋亡指数(apoptosis index,AI)以及临床指标的相关性和预后的意义。方法:免疫组化法检测63例乳腺癌标本中Survivin的表达;TUNEL法检测乳腺癌组织中的AI。结果:Survivin在乳腺癌组织中的表达阳性率为63·5%。Survivin与AI呈负相关,P=0·0000。Survivin与肿块直径、肿瘤分期、雌激素受体状态无关,而与腋窝淋巴结转移呈正相关,P=0·0000。单因素分析显示,Survivin是乳腺癌的一个预后指标,P=0·0115。结论:Survivin是一种有效的凋亡抑制蛋白,在肿瘤的发生过程中起一定作用。检测Survivin对乳腺癌的预后分析和进一步治疗具有指导作用。肿瘤防治杂志,2005,12(19):1476-1479     

Survivin与VEGF在膀胱癌组织中的表达及Survivin ASODN对膀胱癌细胞系的作用

目的检测膀胱癌组织中Survivin、VEGF表达的相关性;观察Survivin反义寡核苷酸（ASODN）对人膀胱癌的作用研究。方法采用免疫组化和蛋白印迹技术,检测41例膀胱癌组织及癌旁非癌组织中Sur-vivin和VEGF的表达;应用SurvivinASODN作用后收集各组细胞。观察细胞形态变化及超微结果变化,检测各组Survivin表达情况、AI和PI及ASODN对细胞的生长抑制率。结果41例患者中29例（67.4%）表达Survivin蛋白,其中25例（61.0%）VEGF表达阳性或弱阳性;在癌周非癌组织中未检测到Survivin蛋白的表达。Survivin与膀胱癌的转移有关,P=0.002;Survivin蛋白的表达与VEGF蛋白的表达有相关性,P=0.001。电镜下ASODN组可见典型凋亡样改变;各ASODN转染组细胞Survivin表达减弱,呈时间与剂量依赖性;ASODN转染组AI和PI与对照组相比差异有统计学意义,P=0.012,而AI和PI在各对照组间差异无统计学意义,P〉0.05。结论Survivin在膀胱癌组织中的表达能促进膀胱癌的发生与发展,并可能通过上调VEGF的表达而促进膀胱癌发展与转移。Survivin ASODN转染后能下调Survivin蛋白表达,诱导癌细胞凋亡,抑制癌细胞增殖。     

Survivin expression by metastatic melanoma predicts poor disease outcome in patients receiving adjuvant polyvalent vaccine

Survivin and livin are members of the inhibitor of apoptosis protein (IAP) family. We hypothesized that elevated expression levels of these 2 IAP genes in resected advanced-stage metastatic melanoma lesions would be associated with poor disease outcome in patients receiving a polyvalent therapeutic cancer vaccine (Canvaxintrade mark). A quantitative real-time RT-PCR (qRT) assay for survivin and livin genes was used to assess mRNA expression in 63 metastatic melanomas obtained during cytoreductive surgery of American Joint Committee on Cancer (AJCC) stage IV melanoma. Nineteen of 63 metastatic melanoma patients received Canvaxin pre- and postoperatively, and 37 patients received only postoperative Canvaxin. Expression of survivin and livin protein was assessed by immunohistochemistry (IHC) and then correlated with mRNA. Survivin mRNA was detected in 62 of 63 (98%) melanoma specimens ranging from 0-5.96 x 10(4) mRNA copies of total RNA. Lower mRNA copy levels of survivin significantly correlated with improved overall survival among the 37 patients who received Canvaxin postoperatively but not preoperatively (log-rank test, p = 0.023). Among patients with low survivin mRNA copies, those who received postoperative Canvaxin did significantly better than patients who received pre- and postoperative Canvaxin (p = 0.003). Livin mRNA was detectable in 60 of 63 (95%) metastatic melanoma specimens but had no significant prognostic utility. These studies demonstrate that lower levels of survivin in recurrent metastatic melanomas are associated with significantly improved survival in patients receiving postoperative adjuvant immunotherapy. Overall, the study indicates survivin expression in metastatic melanomas can significantly influence disease outcome and patient responses to immunotherapy.     

Nuclear survivin expression is associated with HPV-independent carcinogenesis and is an indicator of poor prognosis in oropharyngeal cancer

The relationship between expression of the inhibitor of apoptosis protein survivin and the presence of high-risk human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OSCC) remains unclear. This also accounts for its role as a predictor of survival. Therefore, we conducted a multicentre retrospective study on 106 consecutive oropharyngeal cancer patients. Human papillomavirus sequences were detected by nested PCR protocols. Survivin and p16 expression as a surrogate marker for HPV status were analysed by immunohistochemistry. Sequences of high-risk HPV were detected in 29% of cases. Prominent cytoplasmatic expression of survivin was found in 58% of cases and nuclear expression of survivin was found in 19% of the survivin-positive tumours. Nuclear expression of survivin was significantly correlated with HPV-negative tumours (P=0.023) and with a poor disease-free survival rate with an estimated 3-year disease-free survival probability of 35% for tumours with nuclear expression of survivin vs 78% for tumours with non-nuclear expression of survivin (hazard ratio=8.264; 95% confidence interval (95% CI)=2.510-27.210; P<0.001). In multivariate analysis, p16 expression status as well as nuclear expression of survivin were strong independent and opposing prognostic indicators of disease-free survival (hazard ratio=0.068; 95% CI=0.005-0.892; P=0.041 and hazard ratio=15.975; 95% CI=2.377-107.360; P=0.004, respectively). Our data show that nuclear accumulation of survivin correlates with HPV-independent carcinogenesis and is an independent predictor of poor survival in patients with OSCC.     

Survivin小分子干扰RNA对膀胱癌T24细胞生物学行为的影响

背景与目的:膀胱癌是泌尿系统最常见的恶性肿瘤,通常与体内某些基因突变导致细胞周期改变和抗凋亡机制有关。凋亡抑制蛋白家族(IAPs)的新成员Survivin,通过诱导细胞增殖和抑制细胞凋亡参与了人类多种肿瘤的发生,其中包括膀胱癌。本研究探讨转染靶向survivin的小分子干扰RNA(smallinterfering RNA,siRNA)对膀胱癌生物学行为的影响。方法:设计、合成一对survivin编码基因序列特异的siRNA,用脂质体包裹转染T24膀胱癌细胞,分成不同的浓度组(50～200nmol/L);鼠异位膀胱肿瘤模型中瘤内注射不同剂量的siRNA(5!g和50!g)。分别于体外和体内观察siRNA对膀胱癌生物学行为的影响。结果:survivin编码基因序列特异性siRNA能有效下调survivin基因表达水平,最大效应浓度为100nmol/L,此时survivin表达水平下调了75.91%,并显著的抑制了细胞增殖,抑制率达55.29%,与对照组相比差异有统计学意义(P<0.01)。同时,细胞凋亡率亦由2.8%增加至45.70%,与对照组相比差异有统计学意义(P<0.01)。裸鼠移植瘤内重复多次注射50!g survivin-siRNA能够明显抑制肿瘤生长,与对照相比差异有统计学意义(P<0.01)。结论:survivin-siRNA能显著下调膀胱癌细胞survivin基因表达水平,促进细胞凋亡,抑制肿瘤细胞增殖。     

Survivin: a promising tumor biomarker

Survivin is a 16.5 kDa protein overexpressed in almost all malignancies but rarely detected in normal differentiated adult tissues. Functionally, survivin has been shown to inhibit apoptosis, promote cell proliferation and enhance angiogenesis. Consistent with its role in these processes, survivin has been shown to play a key role in cancer progression. Because of the large difference in expression between normal and malignant tissue and its causal role in cancer progression, survivin is currently undergoing intensive investigation as a potential tumor marker. Emerging data suggests that measurement of survivin can aid the early diagnosis of bladder cancer, determine prognosis in multiple cancer types and predict response to diverse anti-cancer therapies. These preliminary findings on the diagnostic, prognostic and predictive potential of survivin should now be confirmed in large prospective trials. Furthermore, assays for the measurement of survivin should be simplified, standardized and evaluated in external quality assurance schemes.     

Clusterin as a Diagnostic and Prognostic Marker for Transitional Cell Carcinoma of the Bladder

We investigated the feasibility of profiling and measuring the concentration of clusterin in urine and serum for individuals with transitional cell carcinoma (TCC) of the bladder and comparing it with nontumor controls. In addition, we analyzed the correlation of expression of clusterin in specimens of TCC to various clinicopathologic parameters and prognosis of bladder cancer. Blood and urine samples were used from 68 patients with TCC of the bladder and from 61 patients with benign urological diseases. Enzyme-linked immunosorbent assays (ELISA) were performed for clusterin from serum and urine. Quantitation of clusterin mRNA was carried out in 68 bladder tumor specimens from radical cystectomy or transurethral resection and 26 normal bladder specimens from BPH patients by using RT-PCR method. Correlation for the expression of clusterin mRNA with clinicopathologic parameters was analyzed. Serum and urine clusterin was significantly higher in individuals with bladder cancer than control (p = 0.001). Sensitivity and specificity of serum and urine clusterin as a tumor marker for TCC of the bladder was found to be 80%, 91%, 87.1% and 96.7% respectively. Clusterin expression was significantly higher in TCC specimens than normal tissue specimens (P < 0.001). Expression of clusterin was significantly higher in patients with invasive TCC of the bladder than that in patients with superficial TCC and control (P < 0.001). Overexpression of clusterin mRNA was significantly associated with tumor recurrence and overall survival (p < 0.001). The recurrence-free survival time of patients with overexpression of clusterin was significantly shorter than that of patients with weak expression of clusterin (9.8 months vs. 35.2 months). Clusterin may be considered as a potential diagnostic and prognostic biomarker for bladder cancer using urine, serum and/or molecular biology techniques.     

凋亡相关蛋白Survivin及Fas在膀胱移行细胞癌中的表达及其临床意义

目的探讨凋亡相关蛋白Survivin及Fas在膀胱移形细胞癌表达及其临床意义。方法应用S-P免疫组织化学法检测45例膀胱移行细胞癌及10例正常膀胱黏膜组织石蜡切片中Survivin和Fas表达的情况,结合临床资料进行分析。结果Survivin在膀胱移形细胞癌标本中的表达阳性率为68.9%(31/45),而正常对照组中无一例呈阳性表达;Fas在膀胱移行细胞癌标本中的表达阳性率为46.7%(21/45),与对照组阳性率100.0%(10/10)相比,差异有显著性(P<0.05)。Survivin的表达与膀胱移行细胞癌的组织学分级、初发和复发显著相关(P<0.05),但与临床病理分期、肿瘤数目无关;Fas的表达与膀胱移行细胞癌的组织学分级、肿瘤数目、初发和复发相关,但与临床分期无关。相关性分析表明,膀胱移行细胞癌中survivin的表达与Fas表达呈负相关。结论Survivin在膀胱癌组织中选择性表达与膀胱移行细胞癌的分化程度密切相关,Fas蛋白在膀胱移行细胞癌中表达下降,survivin及Fas蛋白对于判断膀胱移行细胞癌预后有重要临床指导意义。     

Expression of survivin in esophageal cancer: correlation with the prognosis and response to chemotherapy

Survivin, a new member of the inhibitor-of-apoptosis (IAP) family, has been reported to be expressed in many cancers but not in differentiated normal tissue. Its expression in esophageal cancer, however, has not been reported. We investigated 51 esophageal cancers and their adjacent normal epithelial tissues for mRNA expression of survivin by RT-PCR. The survivin expression in esophageal cancer tissue was significantly higher than that in normal esophageal tissue (0.211 +/- 0.226 vs. 0.057 +/- 0.135, p < 0.0001). pN4 tumors had significantly higher survivin expression than the pN0-3 tumors (p = 0.0093). Fourteen patients with advanced esophageal cancer had received chemotherapy prior to surgery. The survivin expression in the cancer tissue in patients who achieved a partial response (PR) was significantly lower than that in patients with no change (NC) and in patients with progressive disease (PD; 0.099 +/- 0.134 vs. 0.320 +/- 0.222, p = 0.0434). The median survival for patients with high survivin expression (9.0 months) was less than that for patients with low survivin group expression (30.0 months, p = 0.0023). Survivin expression was one of the significant predictors of survival on univariate analysis (hazard ratio 2.471; 95% confidence interval 1.104-5.533). The results suggest that survivin expression may provide prognostic information in patients with esophageal cancer.