PROMININ-1 (CD133) AS THERAPEUTIC CANCER TARGET

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 鉴定负责癌症进展和转移的癌症干细胞（CSC）亚群（细胞靶点）和发现与恶性表型相关的蛋白质或途径（分子靶点）对于定制适当的全身治疗非常重要。Prominin-1（CD 133）是一种细胞表面糖蛋白，因其位于细胞膜突起上的突出位置而得名，具有识别细胞靶点并构成某些类型癌症的分子靶点的潜力。CD 133现已被认为是迄今为止鉴定的最重要的CSC相关标志物，在多种人类恶性肿瘤的CSC部分中表达增加。CD 133的生理功能是未知的，除了在眼睛中，它参与感光盘形态发生。我们以前已经发现，CD 133敲低减缓了细胞生长，降低了细胞运动性，并降低了人黑色素瘤细胞转移的能力。这些数据以及最近关于抗CD 133-药物偶联物在肝细胞癌和胃癌中的体内抗肿瘤功效的报告11强烈表明：（i）CD 133本身是一个重要的潜在靶点，（ii）靶向CD 133对表达CD 133的肿瘤具有潜在的临床效用。 目前，我们在实验室中正在努力实现以下目标： A.通过酵母双杂交系统发现CD 133蛋白相互作用物。 B。发现CD 133与细胞基因和信号通路的额外（非物理）相互作用。 C.研究抗CD 133免疫毒素和新发现的CD 133相互作用蛋白或CD 133相关信号通路作为癌症治疗干预靶点的潜力。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The identification of the sub-population of cancer stem cells (CSC), responsible for cancer progression and metastasis (cellular target) and the discovery of proteins or pathways relevant to the malignant phenotype (molecular target), are very important to tailor appropriate systemic therapies. Prominin-1 (CD133), a cell-surface glycoprotein, named for its prominent location on the protrusion of cell membranes, has the potential to identify the cellular target and to constitute a molecular target for some types of cancer. CD133 has now been recognized as the most important CSC-associated marker identified so far, with increased expression in the CSC fraction of a large variety of human malignancies. The physiological function(s) of CD133 are unknown, except in the eye, where it is involved in photoreceptor disk morphogenesis. We have previously found that CD133 knockdown slowed cell growth, decreased cell motility, and reduced the capacity of human melanoma cells to metastasize. These data, together with the recent report of in vivo antitumor efficacy of an anti-CD133-drug conjugate in hepatocellular and gastric cancers11, strongly suggest that (i) CD133 is an important potential target per se, and (ii) targeting CD133 has potential clinical utility against CD133-expressing tumors. We are currently pursuing the following aims in our laboratory: A. Discovery of CD133 protein interactors by the yeast "two-hybrid" system. B. Discovery of additional (non-physical) interactions of CD133 with cellular genes and signaling pathways. C. To investigate the potential of anti-CD133 immunotoxins and of newly discovered CD133-interacting proteins or CD133-associated signaling pathways as targets for cancer therapeutic intervention.