microRNAs in Human Cancer

对导致肿瘤发生的基因改变的研究几乎完全集中在 蛋白质编码基因。现在清楚的是，基因组产生了各种非编码RNA，这些RNA具有 在基因调控中扮演着广泛而重要的角色。MicroRNAs是一类丰富的小RNA 通过RNAi途径调节mRNA的表达和稳定性。这些基因中有许多具有 被认为是癌基因和肿瘤抑制因子。在这项计划中，我们建议调查 一个真正的microRNA癌基因的生物学功能，mir-17-92。项目5的最终目标是 了解mir-17-92促进肿瘤发展的确切机制。这将是 通过对microRNA多顺反子的结构-功能研究和通过鉴定 其主要致癌成分的信使核糖核酸靶点。此外，我们还将探索正常的生物学 该癌基因通过功能增益和功能缺失的产生和特征而发挥的作用 功能突变体。最后，我们将更广泛地探讨microrna机制在肿瘤中的作用。 通过对microRNA生物发生机制的遗传操作和通过搜索 乳腺癌、肝细胞癌和B细胞中表达变化的microRNAs 淋巴瘤。

Studies of genetic alterations that contribute to tumor development have focused almost exclusively on protein coding genes. It is now clear that the genome generates a variety of non-coding RNAs that have widespread and important roles in gene regulation. The microRNAs are an abundant class of small RNAs that modulate mRNA expression and stability through the RNAi pathway. A number of these genes have been implicated as oncogenes and tumor suppressors. In this Project, we propose to investigate the biological function on a bona fide microRNA oncogene, mir-17-92. The ultimate goal of Project 5 is to understand the precise mechanism through which mir-17-92 contributes to tumor development. This will be accomplished through structure-function studies of the microRNA polycistron and through the identification of the mRNA targets of its key oncogenic components. Additionally, we will probe the normal biological function of this oncogene through the generation and characterization of both gain-of-function and loss-of- function mutants. Finally, we will explore more broadly the role of the microRNA machinery in tumor development through genetic manipulation of the microRNA biogenesis machinery and through a search for microRNAs that show expression changes in breast carcinoma, hepatocellular carcinoma and B-cell lymphoma.