Department of Surgery, The University of Melbourne, Austin Health, Heidelberg, Victoria, Australia.
PLoS One. 2013;8(1):e54251. doi: 10.1371/journal.pone.0054251. Epub 2013 Jan 16.
Castrate-resistant prostate cancer (CRPC) is a lethal condition in patients receiving androgen deprivation therapy for prostate cancer (PC). Despite numerous studies showing the expression of HIF1α protein under normoxia in PC cell lines, the role of this normoxic HIF1α expression in chemo-resistance and migration has not been investigated previously. As no method is currently available to determine which tumors will progress to CRPC, the role of HIF1α in PC and its potential for predicting the development of CRPC was also investigated.
The effect of HIF1α protein knockdown on chemo-resistance and migration of PC3 cells was assessed by cell counting and Transwell assays, respectively. Translation efficiency of HIF1α mRNA was determined in PC cells using a HIF1α 5'UTR-luciferase construct. Clinical outcomes were correlated following the staining of 100 prostate tumors for HIF1α expression.
The CRPC-like cell lines (PC3 and DU145) expressed more HIF1α protein than an androgen sensitive cell line (LNCaP). Migration rate and chemo-resistance were higher in the PC3 cells and both were decreased when HIF1α expression was reduced. Increased translation of HIF1α mRNA may be responsible for HIF1α overexpression in PC3 cells. Patients whose tumors expressed HIF1α had significantly decreased metastasis-free survival and the patients who were on androgen-deprivation therapy had decreased CRPC-free survival on Kaplan-Meier analysis. On multivariate analysis HIF1α was an independent risk factor for progression to metastatic PC (Hazard ratio (HR) 9.8, p = 0.017) and development of CRPC (HR 10.0, p = 0.021) in patients on androgen-deprivation therapy. Notably the tumors which did not express HIF1α did not metastasize or develop CRPC.
HIF1α is likely to contribute to metastasis and chemo-resistance of CRPC and targeted reduction of HIF1α may increase the responsiveness of CRPCs to chemotherapy. Expression of HIF1α may be a useful screening tool for development of CRPC.
接受雄激素剥夺疗法治疗前列腺癌（PC）的患者中，出现去势抵抗性前列腺癌（CRPC）是一种致命情况。尽管有许多研究表明在 PC 细胞系中常氧条件下 HIF1α 蛋白的表达，但此前尚未研究这种常氧 HIF1α 表达在化疗耐药性和迁移中的作用。由于目前尚无方法确定哪些肿瘤会进展为 CRPC，因此还研究了 HIF1α 在 PC 中的作用及其预测 CRPC 发展的潜力。
通过细胞计数和 Transwell 测定分别评估 HIF1α 蛋白敲低对 PC3 细胞化疗耐药性和迁移的影响。使用 HIF1α 5'UTR-荧光素酶构建体测定 PC 细胞中 HIF1α mRNA 的翻译效率。通过对 100 例前列腺肿瘤进行 HIF1α 染色，对临床结果进行了相关性分析。
CRPC 样细胞系（PC3 和 DU145）比雄激素敏感细胞系（LNCaP）表达更多的 HIF1α 蛋白。PC3 细胞的迁移率和化疗耐药性较高，当 HIF1α 表达减少时，这两种能力均降低。HIF1α mRNA 的翻译增加可能是 PC3 细胞中 HIF1α 过表达的原因。在 Kaplan-Meier 分析中，肿瘤表达 HIF1α 的患者无转移生存时间显著缩短，接受雄激素剥夺治疗的患者无 CRPC 生存时间缩短。多变量分析表明，HIF1α 是接受雄激素剥夺治疗的患者进展为转移性 PC（危险比（HR）9.8，p=0.017）和发生 CRPC（HR 10.0，p=0.021）的独立危险因素。值得注意的是，不表达 HIF1α 的肿瘤不会转移或发展为 CRPC。
HIF1α 可能有助于 CRPC 的转移和化疗耐药性，靶向降低 HIF1α 可能会增加 CRPC 对化疗的敏感性。HIF1α 的表达可能是预测 CRPC 发展的有用筛查工具。
