title: The prognostic value of ribonucleotide reductase small subunit M2 in predicting recurrence for prostate cancers.
abstract: OBJECTIVE
  To investigate the prognostic significance of ribonucleotide reductase small subunit M2 (RRM2) in low- and intermediate-risk prostate cancer (PCa).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Yasheng
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Molecular Pharmacology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA.
authors.forename: Xiyong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of Urology, Department of Surgery, Shuang Ho Hospital, Taipei Medical University, Taipei, Taiwan (R.O.C); Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan (R.O.C).
authors.forename: Yuan-Hung
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Department of Urology, Taipei Medical University; Taipei, Taiwan (R.O.C.).
authors.forename: Shauh-Der
authors.initials: SD
authors.lastname: Yeh
authors.affiliation: Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taiwan (R.O.C.); Department Center of Excellence for Cancer Research, Taipei Medical University, Taipei, Taiwan (R.O.C.).
authors.forename: Chi-Long
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Information Science, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Nelson
authors.affiliation: Department of Pathology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA.
authors.forename: Peiguo
authors.initials: P
authors.lastname: Chu
authors.affiliation: Department of Surgery PS-Urology & Urologic Oncology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Wilson
authors.affiliation: Department of Molecular Pharmacology, City of Hope National Medical Center and Beckman Research Center, Duarte, CA; The Ph.D. Program for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan (R.O.C). Electronic address: yyen@coh.org.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D007150:Immunohistochemistry / Q000706:statistics & numerical data; D053208:Kaplan-Meier Estimate; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011467:Prostate / Q000201:enzymology* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000201:enzymology*; D034622:RNA Interference; D012189:Retrospective Studies; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D048490:raf Kinases; D020780:Matrix Metalloproteinase 9; D018631:ras Proteins
keywords: Biochemical recurrence; Gleason score; Prognostic biomarker; Prostate cancer; Ribonucleotide reductase M2