Nuclear localization of factor inhibitor hypoxia-inducible factor in prostate cancer is associated with poor prognosis.

PURPOSE: We determined the role of factor inhibiting hypoxia-inducible factor-1 in prostate cancer specimens. MATERIALS AND METHODS: A tissue microarray of 152 prostate cancers was constructed and stained for factor inhibiting hypoxia-inducible factor-1, hypoxia-inducible factor-1α and 2α, and glucose transporter 1 as a prototypical downstream target of hypoxia-inducible factor-1α. Correlation analysis was done between these variables, and between factor inhibiting hypoxia-inducible factor-1, and clinical and pathological variables, including prostate specific antigen as a surrogate of recurrence. RESULTS: Factor inhibiting hypoxia-inducible factor-1 was expressed in the cytoplasm and/or the nucleus in 86.5% of tumors, including exclusive cytoplasmic expression in 51.3% and exclusive nuclear expression in 5.3%. Any nuclear and exclusive expression of factor inhibiting hypoxia-inducible factor was associated with poor prognosis on univariate analysis (p = 0.007 and 0.042, respectively). On multivariate analysis men with nuclear expression in tumors were twice as likely to experience recurrence (p = 0.034). CONCLUSIONS: Factor inhibiting hypoxia-inducible factor-1 is widely expressed in prostate tumors. Its differential subcellular expression suggests that regulation of its expression is an important factor in the activity of the hypoxia-inducible factor pathway. Its modulation may help treat hypoxia-inducible factor driven aggressive prostate cancer.

The androgen receptor is significantly associated with vascular endothelial growth factor and hypoxia sensing via hypoxia-inducible factors HIF-1a, HIF-2a, and the prolyl hydroxylases in human prostate cancer.

PURPOSE: Hypoxia regulates key biological processes including angiogenesis via the transcription factor, hypoxia-inducible factor (HIF). In prostate cancer, angiogenesis is also influenced by androgens, and recent cell line studies suggest that this effect is partly mediated by HIF. The study aimed to assess whether a relationship exists in human prostate cancer between expression of the androgen receptor, HIFs, and the key angiogenesis factor, vascular endothelial growth factor (VEGF). EXPERIMENTAL DESIGN: A tissue microarray comprised of 149 radical prostatectomy specimens was constructed. Semiquantitative immunohistochemical analysis was used to assess the expression of the androgen receptor, VEGF and HIF-1a and 2a, and their regulatory prolyl hydroxylase enzymes (PHD1, PHD2, and PHD3). Statistical analysis compared these factors with each other and with prostate-specific antigen relapse. RESULTS: There was a significant correlation between HIF-1a and HIF-2a expression (P = 0.02), and with androgen receptor (P = 0.04 and P < 0.001, respectively) and VEGF expression (P = 0.05 and P < 0.001, respectively). VEGF was also significantly related to the androgen receptor (P = 0.05), whereas PHD2 was inversely related to HIF-2a expression. No significant association was shown between HIF-1a or HIF-2a and time to prostate-specific antigen recurrence (P = 0.20 and P = 0.94, respectively). CONCLUSIONS: These findings confirm the relationship between hypoxia and the androgen receptor in prostate cancer, and show for the first time, the role of HIF-2a in this disease process. They provide clinical evidence to support the recent cell line findings that androgens may regulate VEGF levels through the activation of HIF in androgen-sensitive tumors. Inhibition of both the HIF pathways may provide new therapeutic options in the management of this disease.

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.