Androgen-dependent gene expression of prostate-specific antigen is enhanced synergistically by hypoxia in human prostate cancer cells
Androgen-dependent gene expression of prostate-specific antigen is enhanced synergistically by hypoxia in human prostate cancer cells
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DOI：
10.1158/1541-7786.mcr-06-0226
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发表时间：
2007-04-01
影响因子：
5.2
通讯作者：
Hara, Shuntaro
中科院分区：
文献类型：
--
作者：
Horii, Kou;Suzuki, Yasutomo;Hara, Shuntaro
雄激素受体（AR）与前列腺癌的生长、进展和血管生成有关。缺氧诱导因子-1（HIF-1），转录调节缺氧诱导的血管生成因子，与邻近正常组织相比，在前列腺癌中上调。HIF-1可能参与前列腺癌以及AR，但HIF-1参与前列腺癌血管生成和进展尚未完全阐明。在本研究中，我们发现在前列腺癌LNCaP细胞中，双氢睾酮增强了HIF-1靶基因之一GLUT-1的表达，并且缺氧增强了AR靶基因之一的前列腺特异性抗原（PSA）的表达，并且参与肿瘤侵袭。特异性抑制HIF-1的小干扰RNA降低了PSA和GLUT-1的表达水平。报告基因分析表明，双氢睾酮激活HIF-1介导的基因表达，缺氧增强AR诱导的人PSA基因启动子活性。通过对人PSA基因5 '端侧翼区的缺失和定点突变，发现-3951 ~-3947之间的ACGTG序列是缺氧反应所必需的。染色质免疫沉淀实验表明HIF-1与PSA基因启动子上的AR相互作用。这些结果表明，在前列腺癌中，HIF-1可能与AR协同激活与肿瘤血管生成、侵袭和进展相关的几个基因的表达。
The androgen receptor (AR) is implicated in prostate cancer growth, progression, and angiogenesis. Hypoxia-inducible factor-1 (HIF-1), which transcriptionally regulates hypoxia-inducible angiogenic factors, is up-regulated in prostate cancers compared with adjacent normal tissues. HIF-1 may be involved in prostate cancer as well as the AR, but the involvement of HIF-1 in prostate cancer angiogenesis and progression has not been fully elucidated. In the present study, we found that in prostate cancer LNCaP cells dihydrotestosterone enhanced the expression of GLUT-1, one of the HIF-1 target genes, and also that hypoxia enhanced the expression of prostate-specific antigen (PSA) that is one of the AR target genes and is involved in tumor invasion. Small interfering RNA that specifically inhibits HIF-1 reduced the expression levels of PSA as well as GLUT-1. Reporter gene analysis showed that dihydrotestosterone activated the HIF-1-mediated gene expression and hypoxia enhanced the AR-induced promoter activity of human PSA gene. Deletion and site-directed mutation of the 5'-flanking region of human PSA gene revealed that the sequence ACGTG between -3951 and -3947 was essential in the response to hypoxia. Furthermore, chromatin immunoprecipitation assay indicated that HIF-1 interacts with the AR on the human PSA gene promoter. These results indicated that in prostate cancers, HIF-1 might cooperate with the AR to activate the expression of several genes related to tumor angiogenesis, invasion, and progression.