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


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).


CONCLUSIONS
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.
Dai
Hong
H
Department of Pathology, Baylor College of Medicine, Texas 77030, USA.
Li
Rile
R
Wheeler
Thomas
T
Diaz de Vivar
Andrea
A
Frolov
Anna
A
Tahir
Salahaldin
S
Agoulnik
Irina
I
Thompson
Timothy
T
Rowley
David
D
Ayala
Gustavo
G
D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018450:Disease Progression; D005455:Fluorescent Antibody Technique; D005727:Ganglia, Spinal / Q000473:pathology*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D019394:Ki-67 Antigen; C490587:PIM2 protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D017346:Protein Serine-Threonine Kinases