title: Nuclear factor-kappaB-mediated transforming growth factor-beta-induced expression of vimentin is an independent predictor of biochemical recurrence after radical prostatectomy.
abstract: OBJECTIVE
  Transforming growth factor-beta (TGF-beta)-mediated epithelial-to-mesenchymal transition (EMT) has been shown to occur in some cancers; however, the pathway remains controversial and varies with different cancers. In addition, the mechanisms by which TGF-beta and the EMT contribute to prostate cancer recurrence are largely unknown. In this study, we elucidated TGF-beta-mediated EMT as a predictor of disease recurrence after therapy for prostate cancer, which has not been reported before.
  
  
  METHODS
  We analyzed TGF-beta-induced EMT using nuclear factor-kappaB (NF-kappaB) as an intermediate mediator in prostate cancer cell lines. A total of 287 radical prostatectomy specimens were evaluated using immunohistochemistry in a high-throughput tissue microarray analysis. Levels of TGF-beta signaling components and EMT-related factors were analyzed using specific antibodies. Results were expressed as the percentage of cancer cells that stained positive for a given antibody and were correlated with disease recurrence rates at a mean of 7 years following radical prostatectomy.
  
  
  RESULTS
  In prostate cancer cell lines, TGF-beta-induced EMT was mediated by NF-kappaB signaling. Blockade of NF-kappaB or TGF-beta signaling resulted in abrogation of vimentin expression and inhibition of the invasive capability of these cells. There was high risk of biochemical recurrence associated with tumors that displayed high levels of expression of TGF-beta1, vimentin, and NF-kappaB and low level of cytokeratin 18. This was particularly true for vimentin, which is independent of patients' Gleason score.
  
  
  CONCLUSIONS
  The detection of NF-kappaB-mediated TGF-beta-induced EMT in primary tumors predicts disease recurrence in prostate cancer patients following radical prostatectomy. The changes in TGF-beta signaling and EMT-related factors provide novel molecular markers that may predict prostate cancer outcomes following treatment.
authors.affiliation: Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. q-zhang2@northwestern.edu .
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Brian T
authors.initials: BT
authors.lastname: Helfand
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Jang
authors.forename: Lihua J
authors.initials: LJ
authors.lastname: Zhu
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.forename: Ximing J
authors.initials: XJ
authors.lastname: Yang
authors.forename: James
authors.initials: J
authors.lastname: Kozlowski
authors.forename: Norm
authors.initials: N
authors.lastname: Smith
authors.forename: Shilajit D
authors.initials: SD
authors.lastname: Kundu
authors.forename: Guangyu
authors.initials: G
authors.lastname: Yang
authors.forename: Adekunle A
authors.initials: AA
authors.lastname: Raji
authors.forename: Borko
authors.initials: B
authors.lastname: Javonovic
authors.forename: Michael
authors.initials: M
authors.lastname: Pins
authors.forename: Paul
authors.initials: P
authors.lastname: Lindholm
authors.forename: Yinglu
authors.initials: Y
authors.lastname: Guo
authors.forename: William J
authors.initials: WJ
authors.lastname: Catalona
authors.forename: Chung
authors.initials: C
authors.lastname: Lee
mesh_terms: D000368:Aged; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004848:Epithelium / Q000737:chemistry / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D053538:Keratin-18 / Q000378:metabolism; D008297:Male; D008648:Mesoderm / Q000737:chemistry / Q000473:pathology; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local; D011237:Predictive Value of Tests; D011468:Prostatectomy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D046888:Tissue Array Analysis; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D014746:Vimentin / Q000378:metabolism*
chemical_list: D053538:Keratin-18; D016328:NF-kappa B; D053773:Transforming Growth Factor beta1; D014746:Vimentin