Yasheng Huang1, Xiyong Liu2, Yuan-Hung Wang3, Shauh-Der Yeh4, Chi-Long Chen5, Rebecca A Nelson6, Peiguo Chu7, Timothy Wilson8, Yun Yen9. 1. 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. 2. Department of Molecular Pharmacology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA. 3. 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). 4. Department of Urology, Taipei Medical University; Taipei, Taiwan (R.O.C.). 5. 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.). 6. Department of Information Science, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA. 7. Department of Pathology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA. 8. Department of Surgery PS-Urology & Urologic Oncology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA. 9. 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.
Abstract
PURPOSE: To investigate the prognostic significance of ribonucleotide reductase small subunit M2 (RRM2) in low- and intermediate-risk prostate cancer (PCa). MATERIALS AND 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. CONCLUSION: 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.
PURPOSE: To investigate the prognostic significance of ribonucleotide reductase small subunit M2 (RRM2) in low- and intermediate-risk prostate cancer (PCa). MATERIALS AND 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. CONCLUSION: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.
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