Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
Int J Radiat Oncol Biol Phys. 2013 Nov 15;87(4):753-60. doi: 10.1016/j.ijrobp.2013.07.023. Epub 2013 Sep 10.
We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred.
Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry.
A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001).
AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to tumor regression. HIF1α expression is probably not a useful hypoxia biomarker during ADT in prostate cancer.
在缺氧标记物 pimonidazole 的免疫染色没有明显变化的情况下，我们探讨了雄激素剥夺治疗（ADT）期间雄激素敏感前列腺癌异种移植物中缺氧诱导因子 1（HIF1）信号的变化。
对体积匹配的雄激素暴露和雄激素剥夺的 CWR22 异种移植物的基因表达谱进行比较，这些移植物具有相似的 pimonidazole 阳性分数。通过使用已发表的列表，在差异表达的基因中鉴定出雄激素受体（AR）和 HIF1 转录因子的直接靶标。通过基因本体分析确定 ADT 影响的生物学过程。通过免疫组织化学评估接受新辅助 ADT 的 35 名患者的异种移植物和活检样本中的 HIF1α 蛋白表达。
ADT 导致 1344 个基因的表达变化超过 2 倍，其中包括 35 个下调和 5 个上调的 HIF1 靶标。有 6 个基因是 HIF1 和 AR 的共同靶标，并且通过定量 RT-PCR 证实了它们的下调。在雄激素剥夺的异种移植物中发现了显著抑制增殖、代谢和应激反应等生物学过程，这与肿瘤消退一致。19 个下调的 HIF1 靶标参与了这些重要的生物学过程，其中大多数与代谢有关。这些中有 4 个是 AR 和 HIF1 的共同靶标，包括编码调节糖酵解蛋白 HK2、PFKFB3 和 SLC2A1 的基因。在雄激素反应性前列腺癌细胞系中，大多数下调的 HIF1 靶标被缺氧诱导，证实了它们在前列腺癌中作为缺氧反应性 HIF1 靶标的作用。HIF1 靶标的下调与异种移植物中 HIF1α 蛋白的缺失以及 ADT 引起的患者下调一致（P<.001）。
ADT 对 AR 的抑制可能导致 HIF1 信号的下调独立于缺氧分数，这可能有助于肿瘤消退。HIF1α 表达可能不是前列腺癌 ADT 期间缺氧的有用生物标志物。
