Huang Yasheng, Liu Xiyong, Wang Yuan-Hung, Yeh Shauh-Der, Chen Chi-Long, Nelson Rebecca A, Chu Peiguo, Wilson Timothy, Yen Yun
Department of Urology, Hangzhou Traditional Chinese Medical Hospital, Hangzhou, Zhejiang, China; Department of Molecular Pharmacology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA.
Department of Molecular Pharmacology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA.
Urol Oncol. 2014 Jan;32(1):51.e9-19. doi: 10.1016/j.urolonc.2013.08.002.
To investigate the prognostic significance of ribonucleotide reductase small subunit M2 (RRM2) in low- and intermediate-risk prostate cancer (PCa).
A retrospective outcome study was conducted on 164 eligible PCa samples from the City of Hope (n = 90) and the Taipei Medical University (n = 74). The RRM2 protein levels were detected by immunohistochemistry. Biochemical recurrence was assessed using Kaplan-Meier and Cox proportional hazard analyses. Cell invasion assays, Ras/Raf, and matrix metallopeptidase 9 activities were determined to evaluate the role of RRM2 on invasiveness of PCa.
Expression of RRM2 was significantly increased in patients with higher Gleason score, who had advanced T stage, and who were margin/capsule positive (P<0.05). Analysis revealed that the expression of RRM2 positively associated with biochemical recurrence of PCa in the City of Hope set (hazard ratio = 5.26; 95% CI 1.50-24.71) and the Taipei Medical University set (hazard ratio = 2.55; 95% CI 1.30-9.22). In stratification analysis, RRM2 was significantly correlated with poor outcome in patients with lower-risk PCa, including those with Gleason score 4 to 7, margin(-), capsule(-), and stage T1-T2. In patients with Gleason score 4 to 7, the risk of recurrence was proportional to RRM2 protein levels. The prognostic performance of RRM2 was superior to that of pathoclinical factors, including margin/capsule status and T stage. An in vitro study demonstrated that RRM2 could promote tumor invasion activities in PCa cell lines. Suppression of RRM2 reduced the Ras/Raf and matrix metallopeptidase 9 activities.
RRM2 plays a critical role in proliferation and invasion of PCa. Adding RRM2 as a biomarker in clinical assessments may increase model precision in predicting recurrence in patients with low-risk PCa.
探讨核糖核苷酸还原酶小亚基M2（RRM2）在低危和中危前列腺癌（PCa）中的预后意义。
对来自希望之城（n = 90）和台北医学大学（n = 74）的164例符合条件的PCa样本进行回顾性结局研究。采用免疫组织化学法检测RRM2蛋白水平。使用Kaplan-Meier和Cox比例风险分析评估生化复发情况。通过细胞侵袭试验、Ras/Raf和基质金属肽酶9活性测定来评估RRM2对PCa侵袭性的作用。
RRM2的表达在Gleason评分较高、T分期较晚以及切缘/包膜阳性的患者中显著升高（P<0.05）。分析显示，在希望之城队列（风险比 = 5.26；95%置信区间1.50 - 24.71）和台北医学大学队列（风险比 = 2.55；95%置信区间1.30 - 9.22）中，RRM2的表达与PCa的生化复发呈正相关。在分层分析中，RRM2与低危PCa患者的不良结局显著相关，包括Gleason评分为4至7分、切缘（-）、包膜（-）以及T1 - T2期的患者。在Gleason评分为4至7分的患者中，复发风险与RRM2蛋白水平成正比。RRM2的预后性能优于包括切缘/包膜状态和T分期在内的病理临床因素。体外研究表明，RRM2可促进PCa细胞系的肿瘤侵袭活性。抑制RRM2可降低Ras/Raf和基质金属肽酶9的活性。
RRM2在PCa的增殖和侵袭中起关键作用。在临床评估中添加RRM2作为生物标志物可能会提高预测低危PCa患者复发的模型精度。
