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

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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.