title: Targeting TR4 nuclear receptor suppresses prostate cancer invasion via reduction of infiltrating macrophages with alteration of the TIMP-1/MMP2/MMP9 signals.
abstract: BACKGROUND
  TR4 nuclear receptor 4 (TR4) plays an important role in macrophages-associated foam cell formation of cardiovascular diseases and infiltrating macrophages are critical for prostate cancer (PCa) progression. However, the linkage of macrophages and TR4 and their impacts on PCa metastasis remains unclear.
  
  
  RESULTS
  Knocking-down TR4 in human PCa cells (C4-2, CWR22Rv1), but not in human macrophages cells (THP-1), led to suppress the macrophages infiltration to PCa cells. The consequences of such suppression of the recruitment of macrophages toward PCa then resulted in suppressing the PCa cell invasion. Mechanism dissection found that knocking-down TR4 in PCa cells suppressed metastasis-related genes including MMP2, with induction of TIMP-1. Interruption assays using TIMP-1 neutralizing antibody could then reverse TR4-macrophage-mediated PCa invasion. IHC staining showed higher TR4 level, more macrophage infiltration, lower TIMP-1 and stronger MMP2/MMP9 in tumor tissues of the Gleason score 5 + 4 patients compared with the Gleason score 3 + 3 patients.
  
  
  CONCLUSIONS
  Targeting TR4 in prostate tumor microenvironment might represent a potential new therapeutic approach to better battle PCa metastasis.
authors.affiliation: Department of Urology and Chawnshang Chang Liver Cancer Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. 1291128592@qq.com.|George Whipple Lab for Cancer Research, Departments of Pathology, Urology and Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, 14646, USA. 1291128592@qq.com.
authors.forename: Xianfan
authors.initials: X
authors.lastname: Ding
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology and Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, 14646, USA. doc_ydr@163.com.|Department of Urology, the 2nd Affiliated Hospital of Soochow University, Suzhou, 215004, China. doc_ydr@163.com.
authors.forename: Dong-Rong
authors.initials: DR
authors.lastname: Yang
authors.affiliation: Department of Urology and Chawnshang Chang Liver Cancer Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. xialiqun2008@yahoo.com.cn.
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, School of Medicine, Zhejiang University, Hangzhou, 310016, China. peter1989212@gmail.com.
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, School of Medicine, Zhejiang University, Hangzhou, 310016, China. yushicheng1982@163.com.
authors.forename: Shicheng
authors.initials: S
authors.lastname: Yu
authors.affiliation: Chawnshang Chang Sex Hormone Research Center, Tianjin Institute of Urology, Tianjin Medical University, Tianjin, 300211, China. niuyuanjie9317@163.com.
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, School of Medicine, Zhejiang University, Hangzhou, 310016, China. wmc_32@163.com.
authors.forename: Mingchao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Urology and Chawnshang Chang Liver Cancer Center, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China. ligonghui1970@hotmail.com.
authors.forename: Gonghui
authors.initials: G
authors.lastname: Li
authors.affiliation: George Whipple Lab for Cancer Research, Departments of Pathology, Urology and Radiation Oncology, and The Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, 14646, USA. chang@urmc.rochester.edu.|Sex Hormone Research Center, China Medical University/Hospital, Taichung, 404, Taiwan. chang@urmc.rochester.edu.
authors.forename: Chawnshang
authors.initials: C
authors.lastname: Chang
mesh_terms: D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008264:Macrophages / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D009361:Neoplasm Invasiveness / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011987:Receptors, Steroid / Q000235:genetics*; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics*
chemical_list: C490515:NR2C2 protein, human; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9