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Functional Evidence for a Metastasis Suppressor Gene for Rat Prostate Cancer within a 60-Kilobase Region on Human Chromosome 8p21-p12¹

Laboratory of Biosystems and Cancer, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892 [N. N., N. K., V. L., J. C. B.]; Department of Pathology, University of Washington, Seattle, Washington 98195 [J. O., G. M. M.]; and Department of Molecular Oncology and Department of Urology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan [T. I.]

We recently demonstrated that the human chromosome 8p21-p12 region encodes a metastasis suppressor gene for rat prostate cancer. The presence of this region suppresses the metastatic ability of rat prostate cancer cells (N. Nihei et al., Genes Chromosomes Cancer, 17: 260–268, 1996). To define further the region harboring the metastasis suppressor gene, a truncated human chromosome 8 containing this region was transferred into highly metastatic AT6.3 rat prostate cancer cells by microcell-mediated chromosome transfer. The region of human chromosome 8 retained in each microcell hybrid was determined by a PCR analysis with sequence-tagged site markers, and this analysis placed the metastasis suppressor gene in the interval between D8S2249 and D8S2244 on human chromosome 8p21-p12. One of the metastasis-suppressed microcell hybrids was used for construction of representative yeast/bacterial artificial chromosome (YAC/BAC) library covering the candidate region using a transformation-associated recombination technology (N. Kouprina et al., Genomics, 53: 21–28, 1998). The final contig corresponding to the candidate region was assembled by four YAC/BAC clones. Each clone was transfected into the AT6.3 cells, and the resultant transfectants were tested for their metastatic ability in athymic nude mice. Introduction of a 60-kb YAC/BAC clone resulted in significant suppression of the metastatic ability without suppression of the tumorigenicity. In contrast, other YAC/BAC clones in the contig had neither metastasis nor tumor suppressor activity. This demonstrates that the 60-kb fragment from the human chromosome 8p21-p12 region contains the metastasis suppressor gene for the AT6.3 cells. Frequent loss of heterozygosity of this region is detected in human prostate cancer, which suggests that our target metastasis suppressor gene may also play an important role in the progression of human prostate cancer.

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