Molecular Features of Hormone-Refractory Prostate Cancer Cells by Genome-Wide Gene Expression Profiles

Abstract

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 androgenindependent 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 hormonesensitive 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 SNRPE 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. [Cancer Res 2007;67(11):5117-25]

Analysis of the genomic response of human prostate cancer cells to histone deacetylase inhibitors

“…Tamura et al concluded that expression of HLA-A is downregulated when PCa cells progress from hormone therapy sensitive to hormone resistant PCa. 42 Downregulation of HLA-A may not have occurred in our patients' samples yet, as most cancers are in an early stage when a radical prostatectomy is performed. prevents progression through mitosis if metaphase is not completed properly.…”

Microarray coupled to quantitative RT–PCR analysis of androgen-regulated genes in human LNCaP prostate cancer cells

“…These clusters include many other genes that have not been identified earlier as androgen-responsive genes, and that may play significant roles in prostate cancer biology. Indeed, genes not identified earlier showing strong androgen regulation included the genes for nuclear receptor NR4A1, the cytokine receptor CXCR4 and insulin-like growth factor-1, which have all been implicated in prostate cancer progression (Akashi et al, 2006;Cheng et al, 2006;Tamura et al, 2007). The cluster analysis also indicates that levels of gene regulation by E2 and MPA are similar to those of CPA and OHF, suggesting that E2 and MPA act as SARMs.…”

“…Similarly, expression of the CXCR4 chemokine receptor, which is believed to play a role in cell motility and metastasis, and which has been implicated in many cancer types (Busillo and Benovic, 2007), including prostate cancer, was stimulated 19-fold by R1881 at 24 h, and was stimulated 1.9-2.9-fold by DHT, CPA, OHF and MPA, but was not stimulated by E2. NR4A1 is an orphan nuclear receptor that regulates apoptosis in many cancer cell types (Ke et al, 2004;Chintharlapalli et al, 2005) and whose expression is downregulated in hormone-refractory prostate cancer (Tamura et al, 2007). NR4A1 expression was stimulated 12-fold by R1881, with 1.9-3-fold stimulation by CPA, OHF, E2 and MPA.…”

Gene network and canonical pathway analysis in prostate cancer: a microarray study

“…Moreover, five genes belonging to MHC were strictly downregulated in this network (H2-Q10, HLA-A, HLA-C, HLA-F, and HLA-G). Tamura et al (2007) observed down-regulation of HLA-A antigen in microarray analysis of hormone-refractory prostate cancer. We report the down-regulation of four genes (H2-Q10, HLA-C, HLA-F, and HLA-G) here for the first time.…”