Expression of BNIP3 correlates with hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha and the androgen receptor in prostate cancer and is regulated directly by hypoxia but not androgens in cell lines.
BACKGROUND
BNIP3 is a hypoxia-induced protein involved in cell death and survival but its role in human tumors is unclear. This study investigated the role of BNIP3 in prostate cancer.


METHODS
The expression of BNIP3, the androgen receptor (AR), hypoxia inducible factor (HIF)-1alpha, HIF-2alpha and the hypoxia regulated gene GLUT1 were assessed in tissue microarrays constructed from 149 radical prostatectomy specimens. Statistics compared expression of these factors between each other, conventional clinicopathological parameters and PSA recurrence. Since an association between BNIP3 and AR and the HIFs was observed, the influence of hypoxia, dihydrotestosterone and the AR blocker, Casodex, was also investigated in prostate cell lines.


RESULTS
BNIP3 was expressed in the nucleus and cytoplasm. Eight of 149 (5.5%) tumors showed no expression, 44/149 (29.5%) cases showed exclusively cytoplasmic expression, 17/149 (11.5%) cases showed exclusively nuclear expression and 80/149 (53.5%) cases showed both cytoplasmic and nuclear expression. There was a significant correlation between cytoplasmic BNIP3 expression and Gleason score (P=0.005), age (P=0.02), AR (P=0.001), and GLUT1 (P=0.006). There was a significant correlation between nuclear BNIP3 expression and HIF-1alpha expression (P=0.006) and HIF-2alpha expression (P=0.013) but no correlation between BNIP3 and pre-operative PSA, tumor volume, margin positivity or capsular invasion (all P>0.05). There was an increase in BNIP3 expression under conditions of hypoxia (0.1% 0(2)) but not with dihydrotestosterone stimulation or with Casodex treatment.


CONCLUSIONS
These findings suggest that BNIP3 is directly regulated by hypoxia but that there may be a hormonal independent mechanism coordinating the expression of BNIP3 in prostate tumors.
Shaida
Nadeem
N
Harold Hopkins Department of Urology, Royal Berkshire Hospital, Reading, United Kingdom.
Launchbury
Rosalind
R
Boddy
Jane L
JL
Jones
Catherine
C
Campo
Leticia
L
Turley
Helen
H
Kanga
Suresh
S
Banham
Alison H
AH
Malone
Peter R
PR
Harris
Adrian L
AL
Fox
Stephen B
SB
D000726:Androgen Antagonists / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000813:Anilides / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D009570:Nitriles / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D011944:Receptors, Androgen / Q000096:biosynthesis*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014105:Tosyl Compounds / Q000494:pharmacology; D000099162:Endothelial PAS Domain-Containing Protein 1
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; D051792:Basic Helix-Loop-Helix Proteins; D013196:Dihydrotestosterone; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D009570:Nitriles; D017430:Prostate-Specific Antigen; D011518:Proto-Oncogene Proteins; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D000099162:Endothelial PAS Domain-Containing Protein 1; C410798:AR protein, human; C090121:BNIP3 protein, human; C053541:bicalutamide