Identification of metastasis suppressor genes for prostate cancer and analysis of genetic changes during progression of prostate cancer methamphetamine model---

鉴别前列腺癌转移能力的分子和细胞标记物将有助于开发前列腺癌亚分期的诊断方法。为了分离转移抑制基因，我建立了一个大鼠前列腺癌系统。在这个系统中，我使用微细胞介导的染色体转移技术将正常人类染色体的单个拷贝引入高转移性大鼠前列腺癌。在之前的研究中，我从11p11.2中分离出前列腺癌转移抑制基因KAI1/CD82，证实KAI1/CD82在人类前列腺癌的进展过程中下调。在目前的研究中，我证明了这种下调似乎与甲基化有关。通过同样的方法，我报道了另一个转移抑制基因位于人类染色体8p21-p12区域。在目前的研究中，我从该区域分离出包含转移抑制基因的60kb片段。我还分析了该区域在前列腺癌中的遗传意义，发现该区域的LOH与前列腺癌的进展有关。通过上述方法从17p11.2中鉴定出丝裂原活化蛋白激酶激酶4 （MKK4，一种转移抑制基因）。在这项研究中，我发表了MKK4基因表达与进展中的人类前列腺癌的组织学模式呈负相关。我回顾了前列腺癌的LOH数据，发现通过各种方法一致观察到的常见等位基因丢失位点似乎存在于染色体臂8p、10q、I3q和16q上。我还发现染色体臂12p可能含有前列腺癌的抑癌基因。

Identification of molecular and cellular markers for the metastatic ability of prostate cancer would be useful in developing diagnostic methods for substaging histologically localized prostate cancers. To isolate metastasis suppressor genes, I have established a rat prostate cancer system. In this system, I used a microcell mediated chromosome transfer technique to introduce a single copy of normal human chromosomes into highly metastatic rat prostate cancer.In the previous studies, I isolated KAI1/CD82, a metastasis suppressor gene for prostate cancer, from 11p11.2 and demonstrated that KAI1/CD82 was down-regulated during the progression of human prostate cancer. In the present study, I demonstrate that this down regulation seems to be related to methylation.By using the same method, I reported that another metastasis suppressor gene was located on the human chromosome region 8p21-p12. In the present study, I have isolated the 60-kb fragment from this region that contains the metastasis suppressor gene. I have also analyzed the genetic significance of this region in prostate cancer, and found that LOH of the region is associated with progression of prostate cancer.Mitogen-activated protein kinase kinase 4 (MKK4, a metastasis suppressor gene) was identified from 17p11.2 by the method described above. In this study, I have published that MKK4 gene expression is inversely related to histological pattern in advancing human prostate cancers.I have reviewed LOH data on prostate cancer, and found that common sites of allelic loss that are consistently observed by various methods seem to exist on chromosome arms 8p, 10q, I3q, and 16q. I have also found that chromosome arm 12p may contain tumor suppressor genes for prostate cancer.