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

项目摘要 非裔美国人（AA）男性的转移性去势抵抗性前列腺癌（CRPC）发生率高于男性。 其他男人然而，导致这种差异的遗传学仍然难以捉摸。初步数据显示， CD 24在正常前列腺上皮细胞中不表达，但在高分期PC中过表达， 转移，尤其是AA男性。特别是，CD 24遗传变异体的高表达等位基因更多。 经常出现在AA男性比其他群体。因此，CD 24似乎有助于转移性CRPC， 原子吸收法CD 24的致癌功能已通过异位和/或诱导表达证实， 靶向突变、基因沉默和抗体阻断。值得注意的是，我们开发了一种新的CD 24概念- PC细胞中突变型p53的依赖性失活。由于突变型p53经常与转移性肿瘤相关， CRPC，我们假设CD 24促进突变型p53失活，这有助于肿瘤转移。 AA CRPC患者，将在两个特定目标中进行测试。目的研究CD 24- CRPC细胞中突变型p53对肿瘤转移的依赖性失活。目标二将描述 CD 24、突变型p53与AA CRPC患者肿瘤转移的相关性我们提出的工作将 提供了更好地了解AA中PC侵袭性发病机制的分子机制 并且可用于使处于发展侵袭性CRPC风险的AA男性受益。

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.