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

Prostate. 2005 Nov 1;65(3):276-86. doi: 10.1002/pros.20294.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis / physiology
  • Blotting, Western
  • Cell Line, Tumor
  • Disease Progression
  • Fluorescent Antibody Technique
  • Ganglia, Spinal / pathology*
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing / physiology
  • Humans
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Ki-67 Antigen / metabolism
  • Male
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • Protein-Serine-Threonine Kinases / biosynthesis*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / biosynthesis*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • RNA, Small Interfering / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Up-Regulation

Substances

  • Ki-67 Antigen
  • PIM2 protein, human
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Protein-Serine-Threonine Kinases