Elevated Skp2 protein expression in human prostate cancer: association with loss of the cyclin-dependent kinase inhibitor p27 and PTEN and with reduced recurrence-free survival.
Elevated Skp2 protein expression in human prostate cancer: association with loss of the cyclin-dependent kinase inhibitor p27 and PTEN and with reduced recurrence-free survival.
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发表时间：
2002-11
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通讯作者：
Guang Yang;G. Ayala;A. D. De Marzo;W. Tian;A. Frolov;T. Wheeler;T. Thompson;J. Harper
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作者：
Guang Yang;G. Ayala;A. D. De Marzo;W. Tian;A. Frolov;T. Wheeler;T. Thompson;J. Harper
F-box蛋白Skp2 （Fbl1）是G1-S转化的正调节因子，并促进泛素介导的周期蛋白依赖性激酶抑制剂p27的蛋白水解。在体外和体内模型中，它的过表达与细胞转化和肿瘤发生有关。在这项研究中，我们研究了它在人类前列腺癌进展中的作用。对622例根治性前列腺切除术标本、74例前列腺上皮内肿瘤标本和4例正常前列腺器官供体组装成组织微阵列进行福尔马林固定石蜡切片的免疫组织化学分析。我们发现，正常前列腺的管腔上皮细胞和基底上皮细胞中Skp2水平都很低，但在前列腺上皮内肿瘤癌前病变（P = 0.0252）和前列腺癌（P = 0.0037）中，Skp2水平和标记频率显著升高。Skp2在肿瘤中的标记频率与术前血清前列腺特异性抗原水平（P = 0.0499）和Gleason评分（P = 0.0002）呈正相关，而Skp2指数与前列腺外延伸（P = 0.0454）、临床分期（P = 0.0170）和Gleason评分（P = 0.0002）呈正相关。Kaplan-Meier分析显示，较高的Skp2标记指数（bbb10）是根治性前列腺切除术后较短的生化无复发生存时间的显著预测因子（P < 0.0363， log-rank检验）。研究发现，Skp2与其生化靶标p27在前列腺癌中的表达呈负相关（P = 0.0003），与其推定的负调控因子PTEN抑癌蛋白表达呈负相关（P = 0.0444）。这些数据表明，正如之前的组织培养实验所表明的那样，Skp2的诱导可能与前列腺癌中p27水平的降低有因果关系，并暗示PTEN在体内调节Skp2的表达。
The F-box protein Skp2 (Fbl1) is a positive regulator of G1-S transition and promotes ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27. Its overexpression has been implicated in cell transformation and oncogenesis in both in vitro and in vivo models. In this study, we investigated its role in human prostate cancer progression. Immunohistochemical analysis was performed on formalin-fixed paraffin sections of 622 radical prostatectomy specimens, 74 prostatic intraepithelial neoplasm specimens, as well as in 4 normal prostate organ donors assembled into tissue microarrays. We found that both luminal and basal epithelial cells in normal prostate had very low Skp2 levels, but Skp2 levels and labeling frequency increased dramatically in both premalignant lesions of prostatic intraepithelial neoplasm (P = 0.0252) and in prostate cancer (P = 0.0037). The Skp2 labeling frequency in cancer was positively correlated with preoperative serum prostate-specific antigen level (P = 0.0499) and Gleason score (P = 0.0002), whereas the Skp2 index was positively correlated with extraprostatic extension (P = 0.0454), clinical stage (P = 0.0170), as well as Gleason score (P = 0.0002). Kaplan-Meier analysis revealed that a higher Skp2 labeling index (>10) was a significant predictor of shorter biochemical recurrence-free survival time after radical prostatectomy (P < 0.0363, log-rank test). An inverse correlation of Skp2 was observed with both its biochemical target p27 expression in prostate cancer (P = 0.0003) and with its putative negative regulator, the PTEN tumor suppressor protein (P = 0.0444). These data suggest that induction of Skp2 may be causally linked with decreased levels of p27 in prostate cancer and implicate PTEN in the regulation of Skp2 expression in vivo, as previous tissue culture experiments have suggested.