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Establishment of prediction system for the prognosis of patients with bladder cancer

膀胱癌患者预后预测系统的建立

基本信息

批准号：
16591603
负责人：
NAKAGAWA Masayuki
金额：
$ 2.11万
依托单位：
Kagoshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591603/
关键词：
Bladder cancer invasiveness prognosis SKP2 CKS1 p16INK4a p14ARF DNA methylation DNAマイクロアレイクラスター解析再発

项目摘要

(Purpose) The number of bladder cancer is gradually increasing in Japan. However, the molecular mechanism of bladder cancer progression has not yet fully understood. We attempted to identify genes responsible for tumor progression bladder cancer(Methods and Patients) In this study we enrolled 84 patients who received transurethral resection of bladder tumor (TURBT) and radical cystectomy between 2001 and 2005 in our affiliate hospitals. After obtaining informed consent from all patients, we analyzed the responsible genes for tumor progression in 14 patients with bladder cancer by DNA microarray. For this analysis, we used Ace gene Oligo array (Hitachi Software Engineering Co. Ltd, Yokohama) mounted 30144 genes. We also performed immunohistochemical staining for some candidate genes in tumor tissue specimens. Furthermore, methylation status of promoter region in some candidate genes was examined by methylation specific PCR (MSP)(Results) DNA microarray assay revealed that 21 genes were … More up-regulated and 18 genes were down-regulated in bladder cancer specimens compared with normal bladder tissue. We then confirmed the up-regulation status or down-regulation status of these genes by real-time PCR. Consequently, we picked up 2 genes, S-phase kinase-associated protein 2 (SKP2) and cyclin-dependent kinase subunit 1 (CKS1), as up-regulated genes during the process of bladder cancer progression. The immunohistochemical study demonstrated that expression of SKP2 was similar to that of CKS1 in each tumor specimen, while the expression of p27 was negatively correlated with the expression of these genes. Kaplan-Meier analysis demonstrated that patients with positive expression of either SKP2 or CKS1 had significantly poorer prognosis than the counterparts. MSP analysis revealed that methylation rates of p16INK4a and p14ARF were significantly higher in invasive bladder cancer than those in superficial bladder cancer. Kaplan-Meier analysis demonstrated that patients with p14ARF methylation had significantly poorer prognosis than the counterpart.(Coclusions) Our study suggest that determination of expression levels of SKP2 and CKS1 and methylation status of p16INK4a and p14ARF is useful for prediction of tumor progression and treatment selection in patients with bladder cancer Less

（目的）在日本，膀胱癌的数量正在逐渐增加。然而，膀胱癌进展的分子机制尚不完全清楚。我们试图确定导致膀胱癌肿瘤进展的基因（方法和患者）。在这项研究中，我们招募了84例2001年至2005年间在我们附属医院接受经尿道膀胱肿瘤切除术（turt）和根治性膀胱切除术的患者。在获得所有患者的知情同意后，我们通过DNA芯片分析了14例膀胱癌患者肿瘤进展的相关基因。为了进行分析，我们使用Ace基因Oligo阵列（Hitachi Software Engineering Co., Yokohama）装载30144个基因。我们还对肿瘤组织标本中的一些候选基因进行了免疫组化染色。通过甲基化特异性PCR （methylation specific PCR， MSP）检测了部分候选基因启动子区的甲基化状态。结果DNA微阵列分析显示，膀胱癌组织中有21个基因表达上调，18个基因表达下调。然后我们通过实时PCR确认了这些基因的上调或下调状态。因此，我们发现了2个基因，s期激酶相关蛋白2 （SKP2）和周期蛋白依赖激酶亚单位1 (CKS1)，作为膀胱癌进展过程中的上调基因。免疫组化研究表明，各肿瘤标本中SKP2和CKS1的表达相似，而p27的表达与这些基因的表达呈负相关。Kaplan-Meier分析显示，SKP2或CKS1阳性表达的患者预后明显差于对应的患者。MSP分析显示，p16INK4a和p14ARF在浸润性膀胱癌中的甲基化率明显高于浅表性膀胱癌。Kaplan-Meier分析显示p14ARF甲基化患者的预后明显差于相应的患者。（结论）我们的研究表明，检测SKP2和CKS1的表达水平以及p16INK4a和p14ARF的甲基化状态有助于预测膀胱癌患者的肿瘤进展和治疗选择