title: Testicular orphan nuclear receptor 4 is associated with the radio-sensitivity of prostate cancer.
abstract: BACKGROUND
  It is well known that a significant number of prostate cancers (PCa) showed different extents of radio-resistance and the tumor may recur after treatment. Recent studies demonstrated that Testicular orphan nuclear receptor 4 (TR4) could play a critical role in anti-oxidative stress responses and might modulate the DNA damage repair. The objective of this study is to investigate the role of TR4 in the radiotherapy for PCa.
  
  
  METHODS
  The TR4 expression in tissue samples from PCa patients treated with brachytherapy was measured by immunohistochemistry (IHC). Cell survival test and colony formation assay were applied to test the radio-sensitivity of PCa cells with modulated TR4 gene expression upon irradiation.
  
  
  RESULTS
  PCa patients with biochemical recurrence (BCR) after brachytherapy tend to have higher TR4 expression (80%, n = 30) as compared to those without BCR (36.67%, n = 30). Survival analysis demonstrated a significant higher BCR occurrence in patients with high level of TR4 expression (HR = 3.474, 95%CI 1.678-7.192, P = 0.0008). Multivariate analysis showed that the TR4 staining score on IHC was the only significant variable for predicting the PCa patients' clinical outcomes after radiotherapy (OR = 9.919, 95% CI 2.516-39.101, P = 0.001). Using cell survival test and colony forming assay, we found that the addition of functional TR4 in PC3 cells lead to elevated radio-resistance. In contrast, knocking-down TR4 in LNCaP cells resulted in increased radio-sensitivity. The γH2AX foci kinetic analysis suggested that knocking down TR4 might delay the PCa cell's DNA damage repair which would enhance the radio-sensitivity.
  
  
  CONCLUSIONS
  TR4 could mediate the PCa cells' radio-sensitivity and might become a prognostic indicator for PCa patients received radiotherapy. This study provides a novel approach to manipulate radio-sensitivity of PCa cells, and may bring a promoted therapeutic outcome of radiotherapy to battle PCa in future.
authors.affiliation: Department of Urology and Chawnshang Chang Liver Cancer Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Shicheng
authors.initials: S
authors.lastname: Yu
authors.affiliation: Department of Urology and Chawnshang Chang Liver Cancer Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Mingchao
authors.initials: M
authors.lastname: Wang
authors.affiliation: George Whipple Lab for Cancer Research, Department of Pathology, Urology and Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York.
authors.forename: Xianfan
authors.initials: X
authors.lastname: Ding
authors.affiliation: Department of Urology and Chawnshang Chang Liver Cancer Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Liqun
authors.initials: L
authors.lastname: Xia
authors.affiliation: Department of Urology and Chawnshang Chang Liver Cancer Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Bide
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Urology and Chawnshang Chang Liver Cancer Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Urology and Chawnshang Chang Liver Cancer Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Zhigen
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Chawnshang Chang Sex Hormone Research Center, Department of Urology, The 2nd affiliated hospital of Tianjin Medical University, Tianjin, People's Republic of China.
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Niu
authors.affiliation: Department of Urology and Chawnshang Chang Liver Cancer Center, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
authors.forename: Gonghui
authors.initials: G
authors.lastname: Li
authors.affiliation: George Whipple Lab for Cancer Research, Department of Pathology, Urology and Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, New York.
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000096:biosynthesis*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000502:physiology*; D012097:Repressor Proteins / Q000096:biosynthesis*; D012189:Retrospective Studies
chemical_list: D014408:Biomarkers, Tumor; C472782:NR2C2AP protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins
keywords: prostate cancer; radio-sensitivity; radiotherapy; testicular orphan nuclear receptor 4