Regulation of PCa Stem/Progenitor Cells and Tumor Development by miR-34a

描述(申请人提供)：越来越多的证据表明，各种人类肿瘤含有干细胞样癌细胞群，通常被称为癌症干细胞(CSCs)或肿瘤启动细胞。在过去的几年里，我们的实验室一直专注于人类前列腺癌(PCa)中这种致瘤细胞的鉴定和功能特征。我们的结果清楚地表明，PCa细胞被组织成一个致瘤层次，其中包含相对静止的干细胞样癌细胞亚群，丰富和活跃的肿瘤前体细胞，以及大量分化的PCa细胞。有意义的是，我们观察到CD44+PCa细胞群既包含CSCs，也包含肿瘤前体细胞(即PCa干/祖细胞)。最近，我们致力于了解前列腺癌干细胞/祖细胞是如何被调控的，以及调控分子如何影响体内前列腺癌的发育。例如，在一个项目中，我们已经证明了对ES细胞自我更新和多能性至关重要的Nanog，也在调节前列腺癌(和其他)癌症的干细胞/祖细胞属性和发展中发挥着重要作用。在本项目中，我们证明了一种名为miR-34a的microRNA在PCa干/祖细胞以及PCa发育过程中发挥着关键的负面作用。重要的是，初步数据表明miR-34a通过靶向CD44和Nanog对PCa干/祖细胞产生负面影响。基于我们的初步观察，我们建议在R21的应用中有两个特定的目标：1)进一步研究miR-34a在调节PCa干/祖细胞和肿瘤发展中的作用；2)检验CD44和Nanog代表PCa干/祖细胞中miR-34a的两个关键下游靶点的假设。这些目标将通过结合体内肿瘤实验的一系列细胞生物学和分子方法来实现。这些目标的实现将极大地促进我们对PCa干细胞/祖细胞调控的理解，并为开发新型的抗PCa药物奠定坚实的基础。 与公共健康相关：前列腺癌(PCA)是导致美国男性死亡的头号恶性肿瘤和第二大癌症。越来越多的证据表明，像许多其他实体肿瘤一样，前列腺癌是由被称为癌症干细胞的干细胞提供动力的。在这个项目中，我们证明了一种名为miR-34a的microRNA对PCa干/祖细胞具有负性调节作用，并有效地抑制了PCa的发育。重要的是，miR-34a显示了抗前列腺癌转移的潜在治疗潜力。

DESCRIPTION (provided by applicant): Mounting evidence indicates that various human tumors contain populations of stem-like cancer cells, often termed cancer stem cells (CSCs) or tumor-initiating cells. Our lab, in the past few years, has focused on identification and functional characterizations of such tumorigenic cells in human prostate cancer (PCa). Our results have clearly demonstrated that PCa cells are organized as a tumorigenic hierarchy that contains subsets of relatively quiescent stemlike cancer cells, abundant and actively proliferating tumor progenitors, and the bulk differentiated PCa cells. Of significance, we have observed that the CD44+ PCa cell population contains both CSCs and tumor progenitors (i.e., PCa stem/progenitor cells). Recently, we have directed our efforts to understanding how PCa stem/progenitor cells are regulated and how regulatory molecules impact PCa development in vivo. In one project, for example, we have shown that Nanog, critical for ES cell selfrenewal and pluripotency, also plays an essential role in regulating PCa stem/progenitor cell properties and development of prostate (and other) cancers. In the current project, we show that a microRNA, miR-34a, plays a critical negative role in PCa stem/progenitor cells as well as PCa development. Importantly, preliminary data suggest that miR-34a exerts its negative impact on PCa stem/progenitor cells via targeting CD44 and Nanog. Based on our preliminary observations, we propose, in this R21 application, two Specific Aims: 1) to further study the role of miR-34a in regulating PCa stem/progenitor cells and tumor development; and 2) to test the hypothesis that CD44 and Nanog represent two critical downstream targets of miR-34a in PCa stem/progenitor cells. These aims will be accomplished by a spectrum of cell biological and molecular approaches combined with in vivo tumor experiments. The accomplishment of these goals will greatly advance our understanding of PCa stem/progenitor cell regulation and lay a solid foundation for developing novel anti-PCa therapeutics. PUBLIC HEALTH RELEVANCE: Prostate cancer (PCa) is the number one malignancy that inflicts and second leading cancer that kills American men. Increasing evidence suggests that PCa, like many other solid tumors, is fuelled by stem-like cells called cancer stem cells. In this project, we show that a microRNA, miR-34a, negatively regulates PCa stem/progenitor cells and potently inhibits PCa development. Importantly, miR-34a demonstrates potential therapeutic potential against PCa metastasis.