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Pim-2 upregulation: biological implications associated with disease progression and perinueral invasion in prostate cancer.

Dai H, Li R, Wheeler T, Diaz de Vivar A, Frolov A, Tahir S, Agoulnik I, Thompson T, Rowley D, Ayala G

Department of Pathology, Baylor College of Medicine, Texas 77030, USA.

BACKGROUND: The serine/threonine kinase Pim-2 acts as a transcriptionally regulated apoptotic inhibitor and is implicated in prosurvival. Pim-2 has been implicated in many apoptotic pathways. MATERIALS AND METHODS: Silencer validated short interfering RNA (siRNA) to Pim-2, Silencer GAPDH siRNA, and one scrambled siRNA for eliciting RNAi were transfected separately into DU-145/DRG in vitro model. Total RNA was extracted, purified, and validated by Quantitative RT-PCR 48 hr after transfection. The effects of Pim-2 silencing in vitro were evaluated by Western blot and immunofluroscence and collaborated with Ki-67 and TUNEL. The first microarrays (0.6 mm) had 640 radical prostatectomies while the second array (2 mm) used 226 perineural invasion (PNI) cases. RESULTS: mRNA level of Pim-2 in experimental samples was 99% decreased. The experimental samples (mean 7.6 +/- 0.52%) had significantly higher apoptosis than controls (mean 0.89 +/- 0.014%) (P = 0.000). Conversely, proliferation (Ki-67 index) of the experimental samples (mean 57.1 +/- 3.94%) was lower than controls(mean 64.7 +/- 3.1%), but not significant (P = 0.0979). Both nuclear and cytoplasmic Pim-2 were increased in PNI than in prostate cancer (PCa) away from the nerve. Increased nuclear Pim-2 in PCa was associated with many established prognostic factors. Increased Pim-2 levels (nuclear or cytoplasmic) also correlated with NFkappaB nuclear translocation, higher proliferation, and reduced apoptosis. Higher level of nuclear Pim-2 in the PCa was associated with higher risk of biochemical recurrence (HR: 1.021-2.419, P = 0.0399). CONCLUSION: Pim-2 is an important prosurvival gene, which might result in activation of enhanced anti-apoptotic pathway, leading to a more aggressive phenotype of PCa. Pim-2 may become a target for novel therapeutic strategies.

Published 19 September 2005 in Prostate, 65(3): 276-86.
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