METASTASIS SUPPRESSOR GENE FOR PROSTATIC CANCER

癌症进展到转移状态涉及多个细胞的凋亡。 和基因变化。利用体细胞杂交，我们得到 证明获得转移能力需要 转移抑制功能的丧失和癌基因的激活。 我们已经克隆了一个基因，称为KAI 1，可以抑制转移性 大鼠前列腺癌细胞系的能力而不影响生长 原发肿瘤的发生率。我们正在研究这种基因 以影响人前列腺癌和乳腺癌细胞系的转移。 KAI 1编码一个267个氨基酸的蛋白质， 结构域和一个大的胞外结构域，具有三个潜在的N- 我们已经发现KAI 1在正常人中的表达是高的， 前列腺和乳腺细胞，但在癌细胞系中显著降低 来源于转移性肿瘤我们还发现， 人膀胱、子宫内膜、肺、卵巢和子宫内膜中的蛋白表达， 黑色素瘤癌细胞系。我们正在开发新的抗体试剂， 允许在存档的组织切片中研究KAI 1表达。我们有 收集配对的正常前列腺和肿瘤，以及原发性 乳腺癌患者的乳腺和淋巴结转移， 研究KAI 1表达是否可用于预测转移 原发性癌症的能力。 似乎并不意味着基因突变 KAI 1基因可以解释所观察到的表达降低;我们 目前正在调查其他可能导致KAI 1损失的假设 的功能。这些研究包括改变和机制导致 不稳定的mRNA和蛋白质表达。我们也在确认KAI 1 结合伴侣，以确定它们如何调节KAI 1 功能最后，我们正在开发体内转移试验， 使用各种DNA表达载体来测试KAI 1的能力， 抑制体内转移;可能KAI可用于基因治疗 防止癌症扩散的协议

Progression of cancer to the metastatic state involves multiple cellular and genetic changes. Using somatic cell hybridization, we have demonstrated that acquisition of metastatic ability requires both the loss of metastasis suppressor functions and the activation of oncogenes. We have cloned a gene, termed KAI1, that can suppress the metastatic ability of a rat prostatic cancer cell line without affecting the growth rate of the primary tumor. We are investigating the ability of this gene to effect the metastasis of human prostate and breast cancer cell lines. KAI1 encodes a 267 amino acid protein with four hydrophobic transmembrane domains and a large extracellular domain with three potential N- glycosylation sites.We have found that KAI1 expression is high in normal prostate and breast cells, but is dramatically lower in cancer cell lines derived from metastatic tumors. We have also found reduced or altered protein expression in human bladder, endometrial, lung, ovarian, and melanoma cancer cell lines. We are developing new antibody reagents to allow study of KAI1 expression in archived tissue sections. We have collected matched pairs of normal prostate and tumors, as well as primary breast and lymph node metastases from breast cancer patients to investigate whether KAI1 expression can be used to predict metastatic ability of primary cancers. It does not appear that mutations in the KAI1 gene can account for the decreased expression that is observed; we are currently investigating other hypotheses that would cause KAI1 loss of function. These studies include alterations in and mechanisms leading to unstable mRNA and protein expression. We are also identifying KAI1 binding partners in order to determine how they may regulate KAI1 function. Finally, we are developing in vivo metastasis assays and are using various DNA expression vectors to test the ability of KAI1 to suppress metastasis in vivo; possibly KAI may be used in gene therapy protocols to prevent the spread of cancer.