title: KPNA2 expression is an independent adverse predictor of biochemical recurrence after radical prostatectomy.
abstract: OBJECTIVE
  To analyze rates of expression of karyopherin alpha 2 (KPNA2) in different prostate tissues and to evaluate the prognostic properties for patients with primary prostate cancer.
  
  
  METHODS
  Tissue microarrays (TMA) contained 798 formalin-fixed, paraffin-embedded prostate tissue cores from two different institutes of pathology. TMAs were stained immunohistochemically for KPNA2 and NBS1. SiRNA technologies were used to inhibit KPNA2 expression in vitro, and the effect of this inhibition on cellular viability was determined. Efficiency of knockdown experiments was determined by Western blot analysis.
  
  
  RESULTS
  KPNA2 expression was significantly upregulated in carcinomas of the prostate, especially in metastatic and castration-resistant prostate cancer samples. Positive nuclear KPNA2 immunoreactivity was identified as a novel predictor of biochemical recurrence after radical prostatectomy (n = 348), and was independent of the well-established predictive factors preoperative PSA value, Gleason score, tumor stage, and surgical margin status. These results were validated by analyzing a second and independent prostate cancer cohort (n = 330). Further, in vitro experiments showed that the cell proliferation and viability of PC3 cells was significantly reduced when KPNA2 expression was inhibited. KPNA2 knockdown did not induce PARP cleavage as marker for apoptosis. No significantly increased sub-G(1) fraction could be found by FACS analysis.
  
  
  CONCLUSIONS
  KPNA2 is a novel independent prognostic marker for disease progression after radical prostatectomy. This allows to identify patients who need more aggressive treatment. It can moreover be speculated that patients not suited for surveillance regimens might be identified at initial biopsy by a positive KPNA2 immunohistochemistry.
authors.affiliation: Institute of Surgical Pathology and Department of Urology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Ashkan
authors.initials: A
authors.lastname: Mortezavi
authors.forename: Thomas
authors.initials: T
authors.lastname: Hermanns
authors.forename: Hans-Helge
authors.initials: HH
authors.lastname: Seifert
authors.forename: Martin K
authors.initials: MK
authors.lastname: Baumgartner
authors.forename: Maurizio
authors.initials: M
authors.lastname: Provenzano
authors.forename: Tullio
authors.initials: T
authors.lastname: Sulser
authors.forename: Maximilian
authors.initials: M
authors.lastname: Burger
authors.forename: Matteo
authors.initials: M
authors.lastname: Montani
authors.forename: Kristian
authors.initials: K
authors.lastname: Ikenberg
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Hofstädter
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.forename: Rolf
authors.initials: R
authors.lastname: Jaggi
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000032:analysis; D049109:Cell Proliferation; D002470:Cell Survival; D018450:Disease Progression; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D009687:Nuclear Proteins / Q000032:analysis; D011379:Prognosis; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery*; D034741:RNA, Small Interfering; D015854:Up-Regulation; D028901:alpha Karyopherins / Q000032:analysis* / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C490630:KPNA2 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D028901:alpha Karyopherins