Molecular features of hormone-refractory prostate cancer cells by genome-wide gene expression profiles
Molecular features of hormone-refractory prostate cancer cells by genome-wide gene expression profiles
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DOI：
10.1158/0008-5472.can-06-4040
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发表时间：
2007-06-01
期刊：
影响因子：
11.2
通讯作者：
Nakagawa, Hidewaki
中科院分区：
文献类型：
--
作者：
Tamura, Kenji;Furihata, Mutsuo;Nakagawa, Hidewaki
难治性前列腺癌（HRPC）及其治疗是前列腺癌临床中最关键的问题之一。前列腺癌通常是雄激素依赖性的，对雄激素消融治疗反应良好。然而，在某一阶段，它们最终获得雄激素非依赖性和更具侵袭性的表型，并对任何抗癌疗法表现出不良反应。为了研究临床HRPCs的分子特征，我们采用全基因组cDNA微阵列结合激光微束切割技术分析了25例临床HRPCs和10例前列腺癌敏感性（HSPCs）的基因表达谱。一个无监督的层次聚类分析清楚地区分的表达模式的HRPC细胞的HSPC细胞。此外，无论转移器官如何，来自三名患者的原发性和转移性HRPC紧密聚集。经监督分析和排列检验，HRPCs中有36个基因表达上调，70个基因表达下调（平均差异倍数> 1.5; P < 0.0001）。我们观察到在HRPC进展中AR、ANLN和SNWPE的过度表达以及NR 4A 1、CYP 27 A1和HLA-A抗原的下调。AR过表达可能在前列腺癌难治性表型中发挥核心作用，我们发现的其他基因被认为与临床HRPC的更具侵袭性的表型相关，事实上，通过小干扰RNA敲低这些过表达基因导致前列腺癌细胞活力的急剧衰减。我们对HRPC细胞的微阵列分析应该为理解HRPC进展的分子机制和确定HRPC治疗发展的分子靶点提供有用的信息。
One of the most critical issues in prostate cancer clinic is emerging hormone-refractory prostate cancers (HRPCs) and their management. Prostate cancer is usually androgen dependent and responds well to androgen ablation therapy. However, at a certain stage, they eventually acquire androgen-independent and more aggressive phenotype and show poor response to any anticancer therapies. To characterize the molecular features of clinical HRPCs, we analyzed gene expression profiles of 25 clinical HRPCs and 10 hormone-sensitive prostate cancers (HSPCs) by genome-wide cDNA microarrays combining with laser microbeam microdissection. An unsupervised hierarchical clustering analysis clearly distinguished expression patterns of HRPC cells from those of HSPC cells. In addition, primary and metastatic HRPCs from three patients were closely clustered regardless of metastatic organs. A supervised analysis and permutation test identified 36 up-regulated genes and 70 down-regulated genes in HRPCs compared with HSPCs (average fold difference > 1.5; P < 0.0001). We observed overexpression of AR, ANLN, and SNWPE and down-regulation of NR4A1, CYP27A1, and HLA-A antigen in HRPC progression. AR overexpression is likely to play a central role of hormone-refractory phenotype, and other genes we identified were considered to be related to more aggressive phenotype of clinical HRPCs, and in fact, knockdown of these overexpressing genes by small interfering RNA resulted in drastic attenuation of prostate cancer cell viability. Our microarray analysis of HRPC cells should provide useful information to understand the molecular mechanism of HRPC progression and to identify molecular targets for development of HRPC treatment.