Although various mechanisms of castration-resistant prostate cancer (CRPC) have been discovered, reliable biomarkers for monitoring CRPC progression are lacking. We sought to identify molecules that predict the progression of advanced prostate cancer (AdvPC) into CRPC. The study used primary-site samples (N=45 for next-generation sequencing (NGS); N=243 for real-time polymerase chain reaction) from patients with prostate cancer (PC). Five public databases containing microarray data of AdvPC and CRPC samples were analyzed. The NGS data showed that each progression step in PC associated with distinct gene expression profiles. Androgen receptor (AR) associated with tumorigenesis, advanced progression, and progression into CRPC. Analysis of the paired and unpaired AdvPC and CRPC samples in the NGS cohort showed that 15 genes associated with progression into CRPC. This was validated by cohort-1 and public database analyses. Analysis of the third cohort with AdvPC showed that higher serine peptidase inhibitor, Kazal type 1 (SPINK1) and lower Sp8 transcription factor (SP8) expression associated with progression into CRPC (log-rank test, both P<0.05). Multivariate regression analysis showed that higher SPINK1 (Hazard Ratio (HR)=4.506, 95% confidence intervals (CI)=1.175-17.29, P=0.028) and lower SP8 (HR=0.199, 95% CI=0.063-0.632, P=0.006) expression independently predicted progression into CRPC. Gene network analysis showed that CRPC progression may be mediated through the AR-SPINK1 pathway by a HNF1A-based gene network. Taken together, our results suggest thatSPINK1 and SP8 may be useful for classifying patients with AdvPC who have a higher risk of progressing to CRPC.
Oncotarget. 2017 Nov 06*** epublish ***
Seok Joong Yun, Seon-Kyu Kim, Jayoung Kim, Eun-Jong Cha, Jang-Seong Kim, Sun-Jin Kim, Yun-Sok Ha, Ye-Hwan Kim, Pildu Jeong, Ho Won Kang, Jeong-Hwan Kim, Jong-Lyul Park, Young-Ki Choi, Sung-Kwon Moon, Yung-Hyun Choi, Seon-Young Kim, Wun-Jae Kim
Department of Urology, Chungbuk National University College of Medicine, Cheongju, Korea., Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea., Department of Surgery, Harvard Medical School, Boston, MA, USA., Department of Biomedical Engineering, Chungbuk National University College of Medicine, Cheongju, Korea., Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea., R&D Center, Hanmi Pharm. Co. Ltd., Hwaseong-si, Korea., Department of Urology, School of Medicine, Kyungpook National University, Daegu, Korea., Department of Urology, Chungbuk National University Hospital, Cheongju, Korea., Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Korea., School of Food Science and Technology, Chung-Ang University, Anseong, Korea., Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan, Korea.