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

描述（由申请人提供）：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，通常称为癌症干细胞（CSC）或肿瘤起始细胞。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）中此类致瘤细胞的鉴定和功能表征。我们的研究结果清楚地表明，PCa细胞被组织为一个致瘤层次，其中包含相对静止的干细胞样癌细胞，丰富的和积极增殖的肿瘤祖细胞，和批量分化的PCa细胞的子集。重要的是，我们观察到CD 44 + PCa细胞群含有CSC和肿瘤祖细胞（即，PCa干细胞/祖细胞）。最近，我们致力于了解前列腺癌干/祖细胞是如何调控的，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Nanog对ES细胞自我更新和多能性至关重要，在调节PCa干/祖细胞特性和前列腺（和其他）癌症的发展中也起着重要作用。在目前的项目中，我们发现一种microRNA，miR-34 a，在PCa干/祖细胞以及PCa发育中起着关键的负面作用。重要的是，初步数据表明，miR-34 a通过靶向CD 44和Nanog对PCa干/祖细胞产生负面影响。基于我们的初步观察，我们在R21申请中提出了两个具体目的：1）进一步研究miR-34 a在调节PCa干/祖细胞和肿瘤发展中的作用; 2）检验CD 44和Nanog代表PCa干/祖细胞中miR-34 a的两个关键下游靶点的假设。这些目标将通过一系列细胞生物学和分子方法与体内肿瘤实验相结合来实现。这些目标的实现将极大地推进我们对PCa干/祖细胞调控的理解，并为开发新的抗PCa治疗药物奠定坚实的基础。 公共卫生相关性：前列腺癌（PCa）是造成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，PCa与许多其他实体瘤一样，是由称为癌症干细胞的干细胞样细胞驱动的。在这个项目中，我们发现一种microRNA，miR-34 a，负调控PCa干/祖细胞，并有效地抑制PCa的发展。重要的是，miR-34 a显示出针对PCa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.