Project 1: CD24-dependent Inactivation of Mutant p53 in Metastatic Castration-resistant Prostate Cancer

项目 1：转移性去势抵抗性前列腺癌中突变 p53 的 CD24 依赖性失活

• 批准号: 9357537
• 负责人: Lizhong Wang
• 金额: $ 20.32万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9357537
• 关键词: African American; Alabama; Alleles; Alpha Cell; American; Antibodies; Asians; Bioinformatics; Biological Assay; Biological Markers; CRISPR/Cas technology; Cancer Patient; Cancer cell line; Cell surface; Cessation of life; DU145; Data; Data Set; Death Rate; Development; Diagnosis; Distant Metastasis; Ectopic Expression; Effectiveness; Epithelial Cells; Ethnic group; European; Gene Silencing; Genes; Genetic; Goals; Human; Immunodeficient Mouse; Injection of therapeutic agent; Institution; Louisiana; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Messenger RNA; Metastatic Prostate Cancer; Metastatic to; Modeling; Molecular; Morehouse School of Medicine; Mutate; Mutation; NPM1 gene; Neoplasm Metastasis; North Carolina; Oncogenic; PC3 cell line; Pathogenesis; Patients; Phosphatidylinositols; Pilot Projects; Prostate; Protein p53; Proteins; Race; Resources; Risk; Sampling; Somatic Mutation; Staining method; Stains; Subgroup; TP53 gene; Tail; Technology; Testing; Tumor stage; Universities; Veins; Work; Xenograft procedure; cancer cell; cancer recurrence; cancer type; castration resistant prostate cancer; cell motility; clinically relevant; cohort; disorder risk; experimental study; genetic variant; high risk; inducible gene expression; loss of function; mRNA Expression; men; metastatic process; mouse model; mutant; new therapeutic target; novel; outcome forecast; overexpression; p53 Signaling Pathway; prevent; prostate cancer cell; prostate cancer model; protein expression; therapeutic target; tumor; tumor progression

PROJECT SUMMARY African American (AA) men have a higher rate of metastatic, castration-resistant prostate cancer (CRPC) than other men. However, the genetics contributing to this disparity remain elusive. Our preliminary data show that CD24 is not expressed in normal prostate epithelial cells but is overexpressed in high-stage PC and metastases, especially in AA men. In particular, highly expressed alleles of CD24 genetic variants are more frequently present in AA men than in other groups. Thus, CD24 appears to contribute to metastatic CRPC in AAs. The oncogenic function of CD24 has been demonstrated by ectopic and/or inducible expression, targeted mutations, gene silencing, and antibody blockade. Notably, we developed a new concept of CD24- dependent inactivation of mutant p53 in PC cells. Since mutant p53 is frequently associated with metastatic CRPC, we hypothesize that CD24 promotes mutant p53 inactivation that contributes to tumor metastasis in AA CRPC patients, which will be tested in two specific aims. Aim I will determine the effect of CD24- dependent inactivation of mutant p53 on tumor metastasis in CRPC cells. Aim II will characterize the association between CD24, mutant p53, and tumor metastasis in AA CRPC patients. Our proposed work will provide a better understanding of the molecular mechanisms of the aggressive pathogenesis of PCs in AA men and can be used to benefit AA men at risk of developing aggressive CRPCs.

项目概要 非裔美国人 (AA) 男性患转移性去势抵抗性前列腺癌 (CRPC) 的比例高于男性 其他男人。然而，造成这种差异的遗传学仍然难以捉摸。我们的初步数据表明 CD24 在正常前列腺上皮细胞中不表达，但在高阶段 PC 和 转移，尤其是 AA 男性。特别是，CD24基因变异的高表达等位基因更多 AA 男性中出现的频率高于其他群体。因此，CD24 似乎有助于转移性 CRPC AA。 CD24 的致癌功能已通过异位和/或诱导表达得到证实， 靶向突变、基因沉默和抗体阻断。值得注意的是，我们开发了 CD24 的新概念- PC 细胞中突变型 p53 的依赖性失活。由于 p53 突变体经常与转移相关 CRPC，我们假设 CD24 促进突变 p53 失活，从而导致肿瘤转移 AA CRPC 患者将在两个特定目标上进行测试。目的 我将确定CD24-的效果 突变型 p53 的失活对 CRPC 细胞中肿瘤转移的依赖性。目标 II 将描述 CD24、突变型 p53 与 AA CRPC 患者肿瘤转移之间的关联。我们提出的工作将 更好地了解 AA 中 PC 侵袭性发病机制的分子机制 男性，可用于使有罹患侵袭性 CRPC 风险的 AA 男性受益。