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

¹ Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Departments of ² Urology and ³ Pathology, Kochi University, Kochi Medical School, Nankoku, Japan; ⁴ Laboratory for Medical Informatics, SNP Research Center, RIKEN (Institute of Physical and Chemical Research), Yokohama, Japan; ⁵ Department of Urology, Iwate Medical University, Morioka, Japan; ⁶ Department of Urology, Okayama University, Okayama, Japan; ⁷ Department of Urology, Kanazawa University, Kanazawa, Japan; ⁸ Department of Urology, Nagoya City University, Nagoya, Japan; ⁹ Department of Urology, Ehime University, Shitsukawa, Japan; ¹⁰ Department of Urology, Tsukuba University, Tsukuba, Japan; and ¹¹ Department of Urology, Kyoto Prefectural Medical School, Kyoto, Japan

Requests for reprints: Hidewaki Nakagawa, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5375; Fax: 81-3-5449-5124; E-mail: hidewaki{at}ims.u-tokyo.ac.jp.

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 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]

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