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Molecular features of hormone-refractory prostate cancer cells by genome-wide gene-expression profiles and identification of novel molecular targets for prostate cancer treatment

2007; American Association for Cancer Research; Volume: 67; Linguagem: Inglês

1538-7445

Hidewaki Nakagawa, Kenji Tamura, Suyoun Chung, Motohide Uemura, Mutsuo Furihata, Shingo Ashida, Wataru Obara, Yasutomo Nasu, Hiromi Kumon, Hiroyuki Konaka, Mikio Namiki, Keiichi Tozawa, Kenjiro Kohri, Nozomu Tanji, Masayoshi Yokoyama, Toru Shimai, Hideyuki Akaza, Yoichi Mizutani, Tsuneharu Miki, Tomoaki Fujioka, Taro Shuin, Yusuke Nakamura,

Cancer-related molecular mechanisms research

1484 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 phenotype and show very poor response to any anti-cancer therapies that are presently available. To characterize the molecular features of clinical HRPCs and to identify novel molecular targets for HRPC treatment, we analyzed gene-expression profiles of 25 clinical HRPCs and 10 hormone-sensitive or naive prostate cancers (HSPCs) by genome-wide cDNA microarrays combining with laser microbeam microdisection. An unsupervised clustering analysis clearly distinguished expression patterns of HRPC cells from those of HSPC cells. In addition, primary and metastatic HRPCs from individual patients were closely clustered regardless to metastatic organs. A supervised clustering analysis identified 36 up-regulated genes and 70 down-regulated genes in HRPCs, compared with HSPCs (P 1.5). We observed over-expression of AR, ANLN, and SNRPE, and down-regulation of NR4A1, CYP27A1, and HLA-A antigen in HRPC progression. Such genes were considered to be related to the androgen-independent and more aggressive phenotype of HRPCs. Furthermore, northern blot or immunohistochemistry validated the expression pattern of several over-expression genes in HRPC cells, and we investigated for their functional significance on cancer cell viability by siRNA. They are promising molecular targets for HRPC treatment, including a kinase and several enzymes. Our precise microarray analysis of HRPC cells should provide useful information to understand the molecular mechanism of HRPC progression as well as to identify molecular targets for development of treatment of HRPCs.