The Tumor Suppressive Role of the mir-200 family of microRNAs

描述（由申请人提供）：p53被认为是“基因组的守护者”，因此，这种重要的肿瘤抑制基因的功能丧失是人类癌症中最常见的突变之一1-3。因此，广泛的研究集中在p53信号通路的上下游调节因子和效应因子4-8上。近年来，非编码rna，特别是microrna （mirna）已成为肿瘤抑制网络中不可或缺的组成部分。mirna是一类新的非编码rna，可介导许多mrna的转录后基因沉默。miR-200是一个mirna家族，在两个不同的基因组位点（miR-200b/a/429和miR-200c/141）上有5个成员，在人类乳腺癌和肝癌的p53依赖性肿瘤抑制中发挥重要作用。miR-200抑制上皮-间质转化（epithelial-mesenchymal transition， EMT）的重要调控因子，EMT是上皮肿瘤细胞转移所必需的过程9-11。令人惊讶的是，我的初步数据还表明miR- 200在b细胞淋巴瘤模型中具有肿瘤抑制作用，其肿瘤发生在很大程度上与EMT无关。miR-200活性在E？-myc小鼠Burkitt淋巴瘤模型，E?-myc/+；miR-200c/141-/-小鼠肿瘤发作加速。在这里，我建议使用基因工程miR-200b/a/429和miR-200c/141敲除动物来表征miR-200 mirna在b淋巴瘤中的抑瘤功能。通过小鼠模型和细胞培养研究，我还将描述p53-miR-200轴调控的细胞和分子途径，特别关注miR-200在增殖、凋亡、细胞分化和细胞迁移中的作用。最后，我建议使用生物信息学和实验相结合的方法来确定介导这些肿瘤抑制作用的关键miR- 200靶点。所提出的研究将为B细胞中p53-miR-200轴独特的抑瘤机制提供有价值的信息，这可能导致新的诊断标志物和治疗剂的开发。

DESCRIPTION (provided by applicant): p53 is considered the 'guardian of the genome' and consequently, loss of function of this essential tumor suppressor gene is one of the most common mutations in human cancer1-3. For this reason, extensive studies have focused on the upstream and downstream regulators and effectors of the p53 signaling pathway4-8. Recently, non-coding RNAs, in particular, microRNAs (miRNAs) have emerged as integral components in the tumor suppressor network. miRNAs are a novel class of non-coding RNAs that mediate post-transcriptional gene silencing of many mRNAs. One family of miRNAs, miR-200, consists of five members at two distinct genomic loci (miR-200b/a/429 and miR-200c/141) and plays an important role in p53-dependent tumor suppression in human breast and liver cancer. miR-200 suppresses important regulators for epithelial-mesenchymal transition (EMT), a process required for epithelial tumor cells to metastasize9-11. Surprisingly, my preliminary data also suggest a tumor suppressor role of miR- 200 in a B-cell lymphoma model, whose tumorigenesis is largely independent of EMT. miR-200 activity is down regulated in the E?-myc mouse model for Burkitt Lymphoma, and E?-myc/+; miR-200c/141-/- mice have an accelerated tumor onset. Here I propose to characterize the tumor suppressor functions of the miR-200 miRNAs in B-lymphoma using genetically engineered miR-200b/a/429 and miR-200c/141 knockout animals. Using mouse models and cell culture studies, I will also characterize the cellular and molecular pathways regulated by the p53-miR-200 axis, with particular focus on the role of miR-200 in proliferation, apoptosis, cell differentiation, and cell migration. Lastly I propose to identify th key miR- 200 targets that mediate these tumor suppression effects using a combined bioinformatic and experimental approach. The proposed studies will provide valuable information about the unique tumor suppressor mechanism of the p53-miR-200 axis in B cells, which could lead to the development of new diagnostic markers and therapeutic agents.