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
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
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DOI：
10.1158/1078-0432.ccr-05-0460
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发表时间：
2005-11-01
影响因子：
11.5
通讯作者：
Harris, AL
中科院分区：
文献类型：
--
作者：
Boddy, JL;Fox, SB;Harris, AL
目的：低氧通过转录因子低氧诱导因子（HIF）调节包括血管生成在内的重要生物学过程。在前列腺癌中，血管生成也受到雄激素的影响，最近的细胞系研究表明，这种作用部分是由HIF介导的。该研究旨在评估人类前列腺癌中雄激素受体（HIF）的表达与关键血管生成因子之间是否存在关系，血管内皮生长因子（VEGF）。实验设计：构建了包含149例根治性前列腺切除标本的组织芯片。半定量免疫组化分析用于评估雄激素受体、VEGF和HIF-1a和2a及其调节脯氨酰羟化酶（PHD 1、PHD 2和PHD 3）的表达。结果：HIF-1a和HIF-2a表达与前列腺复发相关（P = 0.02），与雄激素受体（P = 0.04和P < 0.001）和VEGF表达相关（P = 0.05和P <0.001）。VEG F与雄激素受体也显著相关（P = 0.05），而PHD 2与HIF-2a表达呈负相关。HIF-1a和HIF-2a与前列腺特异性抗原复发时间无显著相关性（P = 0.20和P = 0.94，respectively）。结论：这些发现证实了缺氧与前列腺癌雄激素受体之间的关系，并首次显示了HIF-2a在前列腺癌发病过程中的作用。他们提供的临床证据支持最近的细胞系研究结果，即雄激素可能通过激活雄激素敏感性肿瘤中的HIF来调节VEGF水平。抑制这两种HIF途径可能为这种疾病的治疗提供新的治疗选择。
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). VEG F 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.