Hedgehog信号诱导神经前体细胞恶性转化中miRNA的作用及其机制

项目名称： Hedgehog信号诱导神经前体细胞恶性转化中miRNA的作用及其机制

项目编号： No.81472631

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 贾林涛

作者单位： 中国人民解放军第四军医大学

项目金额： 72万元

中文摘要： Hedgehog（Hh）信号的活化与细胞恶性转化密切相关，但其下游机制有待阐明。我们前期以Hh受体Smo转基因小鼠髓母细胞瘤为模型，发现神经前体细胞中Hh途径转录因子Gli2能够转录激活miR-224，而抑癌基因miR-34a则由于HDAC1介导的组蛋白H3K27去乙酰化而显著下调。结合miRNA靶基因研究结果，我们提出Hh信号通过上调miR-224抑制泛素连接酶REN，阻断后者对HDAC1的降解，以组蛋白去乙酰化机制沉默miR-34a，解除了其对包括Smo激活因子GRK2在内的靶基因的抑制作用，从而构成了Hh信号调控的正反馈环路，促进细胞恶性转化。本项目旨在验证上述Hh信号调控环路的存在，进而鉴定Hh/miR-224/REN/HDAC1通路调控的其他靶基因，揭示它们在神经前体细胞恶性转化中的关键作用，为系统认识Hh信号及相关miRNA在神经系统肿瘤演进中的作用提供依据。

中文关键词： C15_脑；中枢神经系统肿瘤；Hedgehog信号；微小RNA；髓母细胞瘤

英文摘要： The activation of Hedgehog (Hh) signaling is pivotally involved in the malignant transformation of cells from various tissues, the underlying mechanism of which remains largely elusive. Using the mouse medulloblastoma model induced by transgenic expression of the Hh receptor Smo, we have established in neural progenitors that miR-224 is transcriptionally activated by the classical Hh pathway transcriptional factor, Gli2, whereas the tumor suppressor, miR-34a, was significantly downregulated due to HDAC1-mediated histone H3K27 deacetylation. Based on the studies concerning candidate miRNA target genes, we propose that Hh signaling upregulates miR-224 to repress its candidate target gene, the ubiqutin ligase REN, which consequently abrogates REN-mediated degradation of HDAC1. Increased cellular HDAC1 leads to epigenetic silencing of tumor suppressors including miR-34a, which in turn enhances the expression of candidate miR-34a targets, e.g. the Smo activator GRK2, thus forming a positive feedback circuit to maintain Hh signaling and promote the proliferation and transformation of neural progenitors. The present study aims to verify the aforementioned regulatory circuit of Hh signaling, to identify other genes regulated by the Hh/miR-224/REN/HDAC1 pathway, and to validate the critical involvement of this pathway in the transformation of neural progenitor cells, which will provide novel insights into the roles of Hh signaling and related miRNAs in the progression of the nervous system malignancies.

英文关键词： malignancies in the central nervous system;Hedgehog signaling;miRNA;medulloblastoma