Metastasis Suppressor Genes for Prostate Cancer

癌症进展到转移状态涉及多种细胞和遗传变化。转移能力的获得需要转移抑制功能的丧失以及转移促进功能的活化。从转移抑制基因的染色体定位开始，然后结合位置和功能克隆策略，我们确定了KAI 1，一个抑制大鼠前列腺癌模型转移能力的人类基因。KAI 1在人类肿瘤转移中的意义通过与其正常或非转移性对应物相比，KAI 1在各种组织来源的转移性肿瘤中的表达显著降低来显示，表明KAI 1是极好的诊断和预后标志物。KAI 1结合配偶体的鉴定（例如，E-cadherin和catenins）的酵母双杂交和免疫共沉淀试验提供了KAI 1功能的分子细节的线索。我们最近利用同样的实验系统克隆了另一个转移抑制基因Tey 1，位于人类染色体8 p21，在许多类型的人类癌症中经常观察到洛。Tey 1抑制转移的细胞和分子机制正在研究中。我们还通过全基因组基因表达谱研究了受KAI 1和Tey 1调节的信号通路控制的下游靶基因。

Progression of cancers to the metastatic state involves multiple cellular and genetic changes. Acquisition of metastatic ability requires loss of metastasis suppressor functions, as well as activation of metastasis promoting functions. Starting from the chromosome mapping of metastasis suppressor genes, followed by a combination of positional and functional cloning strategies, we identified KAI1, a human gene that suppresses the metastatic ability in a rat prostate cancer model. The significance of KAI1 in human tumor metastasis was shown by the marked decrease in KAI1 expression in metastatic tumors of various tissue origins compared with their normal or non-metastatic counterparts, suggesting KAI1 as an excellent diagnostic and prognostic marker. Identification of the KAI1 binding partners (e.g., E-cadherin and catenins) by yeast two-hybrid and co-immunoprecipitation assays provided clues to molecular details of the KAI1 function. By using the same experimental system, we have recently cloned another metastasis suppressor gene, termed Tey1, on human chromosome 8p21, where LOH is frequently observed in many types of human cancers. Cellular and molecular mechanisms by which Tey1 suppresses metastasis are under investigation. We are also investigating, by genome-wide gene expression profiling, downstream target genes that are controlled by KAI1- and Tey1-regulated signaling pathways.