| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥300,000)
Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2006: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Research 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 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 prostate cancers (HSPCs) by genome-wide cDNA microarrays combining with 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 7
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0 down-regulated genes in HRPCs, compared with HSPCs, including over-expression of AR, ANLN, and SNRPE, and down-regulation of NR4A1, CYP27A1, and HLA-A antigen. They were considered to be related to the androgen-independent and more aggressive phenotype of HRPCs. Among them, we characterized a novel gene, SRD5A3, encoding a putative 5α-steroid reductase that produces the most potent androgen DHT (5α-dihydrotestosterone) from testosterone. LC-MS/MS analysis following in vitro 5α-steroid reductase reaction validated its ability to produce DHT from testosterone as similar to type-1 5α-steroid reductase. RT-PCR and northern blot analyses confirmed its over-expression in HRPC cells, and indicated no or little expression in normal adult organs. Knockdown of SRD5A3 expression by siRNA in prostate cancer cells resulted in significant decrease of DHT production and drastic reduction of their cell viability. These findings implicate that a novel type-3 5α-steroid reductase, SRD5A3, is associated with DHT production and maintenance of the AR pathway activation in HRPC cells. Our precise microarray analysis of HRPC cells should provide useful information to better understand the molecular mechanism of HRPC progression as well as to identify molecular targets for development of treatment of HRPCs. Less
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