Metastasis Suppressor Genes For Prostate Cancer

癌症向转移状态的进展涉及多种细胞和基因变化。转移能力的获得需要转移抑制功能的丧失和转移促进功能的激活。从肿瘤转移抑制基因的染色体定位入手，结合定位和功能克隆策略，我们鉴定了KAI1，这是一个在大鼠前列腺癌模型中抑制转移能力的人类基因。KAI1在人类肿瘤转移中的意义表现为KAI1在不同组织来源的转移性肿瘤中的表达明显低于正常或非转移性肿瘤，提示KAI1是一个良好的诊断和预后标志物。通过酵母双杂交和免疫共沉淀法鉴定KAI1结合伙伴(如E-钙粘附素和连接素)，为了解KAI1功能的分子细节提供了线索。通过使用相同的实验系统，我们最近在人类染色体8p21上克隆了另一个转移抑制基因Tey1，该基因在许多类型的人类癌症中经常被观察到LOH。Tey1抑制肿瘤转移的细胞和分子机制正在研究中。我们还在通过全基因组基因表达谱研究由KAI1和Tey1调控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.