Mechanism of loss of androgen dependency in prostate cancer, related to its proliferation and expansion

本课题的研究成果如下：1。基因多态性分析可能在前列腺癌发展的个体易感性中起重要作用。1) 1期催化酶中的CYP 1A1和2期偶联酶中的NAT1发生前列腺癌的风险显著增高。此外，CYP 1与偶联酶组之一GSTM1的结合增加了前列腺癌发生的风险。2)参与类固醇代谢的酶基因cyp17的频率越高，患前列腺癌的风险越高。使用Ki-67抗原、bc1-2和p53癌蛋白表达的免疫组织化学分析预测前列腺癌的疾病进展Ki-67标记指数是预测早期内分泌治疗后PSA失败或晚期前列腺癌最有用的指标。前列腺癌患者8p染色体的分子遗传学分析。D8S201（48%）、LPL（48%）和DCC（26%）的杂合性经常缺失。在B、C和d期，28%的患者出现微卫星不稳定。8p染色体上的未知基因可能参与了前列腺癌的发生。雄激素非依赖型前列腺癌细胞α6整合素基因表达中丝裂原活化蛋白激酶（MAP激酶）通路的研究Sp1在转录起始位点-48 ~ 43 bp的一致序列是α6整合素基础启动子活性所必需的，提示从MAP激酶到Sp1激活的信号转导可能参与了雄激素非依赖性前列腺癌细胞α6整合素的表达。

The results of the research project are as follows :1. Anaysis of genetic polymorphisms which may play an important role in individual susceptability with regard to prostate cancer development. 1) CYP 1A1 among catalyzing enzymes in the phase 1 and NAT1 among conjugating enzymes in the phase 2 had a significantly higher risk of prostate cancer. Moreover, combination of CYP 1 and GSTM1, one of conjugating enzyme groups, increased the risk of prostate cancer development. 2) A higher frequency of CYP 17, an enzyme gene involved in steroid metabolism, was associated with the higher risk of prostate cancer.2. Immunohistochemical analysis using expressions of Ki-67 antigen, bc1-2 and p53 oncoproteins to predict disease progression in prostate cancer. Ki-67 labeling index was the most useful parameter to predict PSA failure or the advanced prostate cancer after the initial endocrine therapy.3. Molecular genetic analysis of chromosome 8p in prostate cancer patients. Frequent loss of heterozygosity was observed for D8S201 (48%), LPL (48%) and DCC(26%). Microsatellite instability was observed in 28% in stages B, C and D.Unidentified genes on chromosome 8p may be involved in carcinogenesis of the prostate.4. Investigation of mitogen-activated protein kinases (MAP kinase) pathway involving in the α6 integrin gene expression in androgen-independent prostate cancer cell lines. Sp1 consensus sequence at -48 to 43 bp from the transcription start site was necessary for basal promoter activity of the α6 integrin, suggesting that signal transduction from MAP kinases to activation of Sp1 might involved in α6 integrin expression in androgen-independent prostate cancer cell lines.