Expression of the forkhead transcription factor FOXP1 is associated both with hypoxia inducible factors (HIFs) and the androgen receptor in prostate cancer but is not directly regulated by androgens or hypoxia
Expression of the forkhead transcription factor FOXP1 is associated both with hypoxia inducible factors (HIFs) and the androgen receptor in prostate cancer but is not directly regulated by androgens or hypoxia
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DOI：
10.1002/pros.20583
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发表时间：
2007-07-01
期刊：
影响因子：
2.8
通讯作者：
Fox, Stephen B.
中科院分区：
文献类型：
--
作者：
Banham, Alison H.;Boddy, Jane;Fox, Stephen B.
背景FOXP 1是有翼螺旋或叉头转录因子的成员。最近的研究表明，FOXP 1作为一个候选的肿瘤抑制基因和潜在的雌激素受体（ER）的协同调节在乳腺癌的发展可能发挥作用。本研究调查FOXP 1是否与前列腺癌中的雄激素受体（AR）有类似的关系，以及这些因素如何与缺氧的存在相关。FOXP 1、AR和各种低氧调节蛋白（HIF-1 α、HTF-2 α和VEGF）用组织微阵列技术测量，该组织微阵列由167个存档的根治性切除术构建。统计学分析比较了这些因素的共同表达与其他常规参数，包括患者年龄，术前前列腺特异性抗原（PSA），术后Gleason评分，包膜浸润，手术切缘状态，肿瘤体积和PSA复发。研究了缺氧、双氢睾酮和AR阻滞剂Casodex在前列腺细胞系VCaP和LNCaP中的体外影响。核FOXP 1表达与AR（P = 0.0001）、缺氧诱导因子1 α（P = 0.01）、缺氧诱导因子2 α（P = 0.0001）和血管内皮生长因子（P = 0.007）表达显著正相关。与术后Gleason评分也有显著正相关（P = 0.03），但与其他变量，包括PSA复发无显著相关性（P > 0.05）。在缺氧（0.1%）、双氢睾酮刺激（10或100 nM）或Casodex雄激素阻断（1、10或50 μ M）条件下，FOXP 1蛋白水平的表达无显著变化。这些发现表明，在前列腺肿瘤中可能存在一种激素和缺氧独立的调节机制，协调HIF、AR和FOXP 1的表达。
BACKGROUND. FOXP1 is a member of the winged helix or forkhead transcription factors. Recent studies have indicated possible roles for FOXP1 as a candidate tumor suppressor gene and a potential estrogen receptor (ER) co-regulator in the development of breast cancer. This study investigated whether FOXP1 has a similar relationship to the androgen receptor (AR) in prostate cancer and how these factors relate to the presence of hypoxia.METHODS. FOXP1, the AR and various hypoxia-regulated proteins (HIF-1 alpha, HTF-2 alpha, and VEGF) were measured with immunohistochernistry using a tissue microarray constructed from 167 archival radical prostatectomies. Statistical analyses compared the co-expression of these factors both with each other and conventional parameters including patient age, pre-operative prostate specific antigen (PSA), post-operative Gleason score, capsular invasion, surgical margin status, tumor volume, and PSA recurrence. The influence of hypoxia, dihydrotestosterone, and the AR blocker Casodex was investigated in prostate cell lines VCaP and LNCaP in vitro.RESULTS. Expression of nuclear FOXP1 was significantly positively correlated with AR (P = 0.0001), hypoxia inducible factor 1 alpha (HIF-1 alpha) (P = 0.01), HIF-2 alpha (P = 0.0001), and vascular endothelial growth factor (VEGF) (P = 0.007) expression. A positive significant relationship was also identified with the post-operative Gleason score (P = 0.03) but not with the other variables, including PSA recurrence (P > 0.05). There was no significant change in expression in FOXP1 protein levels under conditions of hypoxia (0.1%), dihydrotestosterone stimulation (10 or 100 nM), or androgen blockade with Casodex (1, 10, or 50 mu M).CONCLUSION. These findings suggest that there may be a hormonal and hypoxia independent regulatory mechanism coordinating the expression of HIFs, the AR, and FOXP1 in prostate tumors.