Abstract

PURPOSE: 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. EXPERIMENTAL DESIGN: Tissue microarrays containing 798 formalin-fixed, paraffin-embedded prostate tissue cores from two different institutes of pathology. TMAs were stained immunhistochemically 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. Efficency of knock down 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 poly(ADP-ribose) polymerase (PARP) cleavage as marker for apoptosis. No significantly increased subG1 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.