叉头转录因子FOXP1的表达与前列腺癌中的缺氧诱导因子（HIFs）和雄激素受体均相关，但不受雄激素或缺氧的直接调控。

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.

作者信息

Banham Alison H, Boddy Jane, Launchbury Rosalind, Han Cheng, Turley Helen, Malone Peter R, Harris Adrian L, Fox Stephen B

机构信息

Nuffield Department Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.

出版信息

Prostate. 2007 Jul 1;67(10):1091-8. doi: 10.1002/pros.20583.

DOI:10.1002/pros.20583

PMID:17477366

Abstract

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-1alpha, HIF-2alpha, and VEGF) were measured with immunohistochemistry 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 1alpha (HIF-1alpha) (P = 0.01), HIF-2alpha (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 microM).

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.

摘要

背景

FOXP1是翼状螺旋或叉头转录因子家族的一员。最近的研究表明，FOXP1可能作为候选肿瘤抑制基因以及在乳腺癌发生发展过程中潜在的雌激素受体（ER）共调节因子发挥作用。本研究调查了FOXP1在前列腺癌中与雄激素受体（AR）是否存在类似关系，以及这些因子与缺氧状态如何相关。

方法

使用由167例存档根治性前列腺切除术构建的组织芯片，通过免疫组织化学法检测FOXP1、AR以及各种缺氧调节蛋白（HIF-1α、HIF-2α和VEGF）。统计分析比较了这些因子之间的共表达情况以及与包括患者年龄、术前前列腺特异性抗原（PSA）、术后Gleason评分、包膜侵犯、手术切缘状态、肿瘤体积和PSA复发等传统参数的关系。在前列腺癌细胞系VCaP和LNCaP中体外研究了缺氧、二氢睾酮和AR阻滞剂比卡鲁胺的影响。

结果

核FOXP1的表达与AR（P = 0.0001）、缺氧诱导因子1α（HIF-1α）（P = 0.01）、HIF-2α（P = 0.0001）和血管内皮生长因子（VEGF）（P = 0.007）的表达显著正相关。还发现与术后Gleason评分呈显著正相关（P = 0.03），但与其他变量无关，包括PSA复发（P > 0.05）。在缺氧（0.1%）、二氢睾酮刺激（10或100 nM）或用比卡鲁胺（1、10或50 μM）进行雄激素阻断的条件下，FOXP1蛋白水平的表达没有显著变化。