Segawa Takehiko, Nau Martin E, Xu Linda L, Chilukuri Rao N, Makarem Mazen, Zhang Wei, Petrovics Gyorgy, Sesterhenn Isabell A, McLeod David G, Moul Judd W, Vahey Maryanne, Srivastava Shiv
Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Rockville, Maryland, MD 20852, USA.
Oncogene. 2002 Dec 12;21(57):8749-58. doi: 10.1038/sj.onc.1205992.
Evaluations of androgen regulated gene (ARG) repertoire provide new insights into the androgen receptor (AR) mediated signaling at the transcriptional level. Definition of ARGs having critical functions in the biology of normal and malignant prostate should aid in identifying new bio-markers and therapeutic targets for prostate cancer (CaP). Using Affymetrix HuGene FL oligonucleotide arrays, temporal expression profiles of ARGs in widely used hormone responsive LNCaP cells, were analysed by hierarchical clustering methods and functional classification. ARGs in response to different androgen concentrations showed temporal co-regulation of genes involved in specific biochemical pathways. This study focuses on our new observations of the coordinated androgen induction of genes (NDRG1, PDIR, HERPUD1, ORP150) involved in the endoplasmic reticulum (ER) stress response pathway. Expression analysis of the two selected ER stress responsive genes, NDRG1 and HERPUD1 in primary CaPs revealed a significantly reduced tumor associated expression. Intriguing linkage of the androgen signaling to ER stress responsive genes, a protective response to protein unfolding or protein damage resulting from cellular stress signals, suggests that androgens may induce such stress signals in CaP cells. Decreased CaP associated expression of two ER stress responsive genes also suggests that possible abrogation of this pathway in prostate tumorigenesis.
雄激素调节基因（ARG）库的评估为雄激素受体（AR）介导的转录水平信号传导提供了新的见解。确定在正常和恶性前列腺生物学中具有关键功能的ARGs应有助于识别前列腺癌（CaP）的新生物标志物和治疗靶点。使用Affymetrix HuGene FL寡核苷酸阵列，通过层次聚类方法和功能分类分析了广泛使用的激素反应性LNCaP细胞中ARGs的时间表达谱。对不同雄激素浓度有反应的ARGs显示出参与特定生化途径的基因的时间共调节。本研究重点关注我们对参与内质网（ER）应激反应途径的基因（NDRG1、PDIR、HERPUD1、ORP150）的协同雄激素诱导的新观察结果。对原发性CaP中两个选定的ER应激反应基因NDRG1和HERPUD1的表达分析显示，肿瘤相关表达显著降低。雄激素信号与ER应激反应基因的有趣联系，即对细胞应激信号导致的蛋白质解折叠或蛋白质损伤的保护性反应，表明雄激素可能在CaP细胞中诱导这种应激信号。两个ER应激反应基因的CaP相关表达降低也表明在前列腺肿瘤发生过程中该途径可能被废除。
