FUNCTION OF C-CAM IN PROSTATE CANCER

细胞黏附分子(CAM)在细胞周期中发挥重要作用 多细胞生物的发育和分化。 最近的研究表明，CAM基因或其基因的缺陷 其表达可能与肿瘤的进展有关。C-CAM是一种 免疫球蛋白超基因家族的上皮细胞黏附分子。我们的研究表明 在前列腺中，C-CAM主要表达在上皮细胞和 它的表达受雄激素的调节。下调监管或 在前列腺中观察到C-CAM的表达完全丧失 上皮内瘤变(PIN)和前列腺癌，提示 C-CAM在维持正常的前列腺组织中可能是必不可少的。 与此观察一致的是，我们证明了转基因 将C-CAM1导入前列腺癌细胞系。PC-3或DU145 显著降低了它们的致瘤性。相比之下，转染人 C-CAM1反义基因导入非致瘤NBE细胞 使它们具有致瘤性。这些结果表明，C-CAM1 具有生长抑制作用。 基于这些结果，我们建议对其机理进行研究。 C-CAM1对前列腺癌生长和致瘤性的影响 癌细胞。C-CAM1可能抑制前列腺癌的致瘤性 癌细胞，因为C-CAM1的表达激活了一种信号 改变这些细胞“分化状态”的途径 从而干扰肿瘤细胞的生长。我们之前曾提议 通过缺失来描述C-CAM中的肿瘤抑制结构域 分析。我们已经实现了这一目标，并表明C- 胞质末端结构域，但不存在细胞外黏附 C-CAM1结构域在介导其抑瘤作用中起关键作用 活动。我们还提出了鉴定和克隆细胞蛋白的建议 与C-CAM1相互作用。多个候选人互动 分子已经被识别出来。我们计划通过以下方式继续这项研究 实现以下具体目标：1.确定 C-CAM1的胞质结构域是否足以 引发肿瘤抑制。我们已经证明了细胞质 C-CAM的结构域是肿瘤抑制所必需的。 这个细胞质结构域本身是否足以 活动尚不清楚。我们将研究这一点的影响 细胞质结构域(在没有其他结构域的情况下 CAM1)对相互作用蛋白的影响。几个候选的C-CAM1- 相互作用的蛋白质已经通过化学交联来鉴定， 酵母双杂交和表达文库筛选方法。我们 将进一步确定这些蛋白质的特征并执行功能 评估它们在C-CAM1介导的生长中的作用的方法 压制。

Cell adhesion molecules (CAMs) play critical roles in the development and differentiation of multicellular organisms. Recent studies indicate that defects in CAM genes or in their expression may be related to cancer progression. C-CAM is an epithelial CAM of the Ig supergene family. Our studies show that in prostate C-CAM is mainly expressed in the epithelial cells and its expression is regulated by androgen. Down-regulation or complete loss of C-CAM expression was observed in prostate intraepithelial neoplasia (PIN) and prostate cancer, suggesting that C-CAM may be essential in maintinaing a normal prostate. Consistent with this observation, we demonstrated that transfection of C-CAM1 into the prostate cancer cell lines. PC-3 or DU145 markedly reduced their tumorigenicity. In contrast, transfection of a C-CAM1 antisense gene into a non-tumorigenic NbE cells rendered them tumorigenic. These results suggest that C-CAM1 has growth suppressive function. Based on these results, we propose to investigate the mechanims by which C-CAM1affects the growth and tumorigenicity of prostate cancer cells. C-CAM1 may suppress the tumorigenicity of prostate cancer cells because expression of C-CAM1 activates a signaling pathway that changes the "diferentiation state" of these cells and thus interferes with tumor cell growth. We previously proposed to delineate the tumor suppressor domain in C-CAM by deletion analysis. We have accomplished this goal and showed that the C- terminal cytoplasmic domain but ot the extracellular adhesion domain of C-CAM1 is critical in mediating its tumor-suppressive activity. We also proposed to identify and clone cellular proteins that interact with C-CAM1. Several candidate interacting molecules have been identified. We plan to continue this study by accomplishing the following Specific Aims: 1. To determine whether the cytoplasmic domain of C-CAM1 is sufficient for eliciting tumor suppression. We have shown that the cytoplasmic domain of C-CAM is required for the tumor suppression. Whether this cytoplasmic domain by itself is sufficient for this activity is not clear. We will examine the effects of this cytoplasmic domain (in the absence of other domains from C- CAM1) on interacting proteins. Several candidate C-CAM1- interacting proteins have been identified by chemical cross-linking, yeast two-hybrid, and expression library screening approaches. We will further characterize these proteins and perform functional assays to assess their roles in C-CAM1-mediated growth suppression.