共同分子机制的反向表达调控引发的反向生物学效应是神经退行性疾病降低癌症风险的重要原因

Epidemiological studies have demonstrated that patients with neuron-degenerative diseases have a reduced risk of cancer. however, the molecular mechanism still remains unknown. A review study showed that some miRNAs、genes and pathways are reversely expressed and regulated.These results further indicated a common mechanism with opposing effects may be the cause of the adverse association between neuron-degenerative diseases and cancers. The investigator has discovered perturbation of some important biological processes and subnetwork that serves as the core mechanisms in the development of a typical neuron-degenerative disease via comprehensive analyses on transcriptome studies of postmortem brain tissues at distinctive stages. the aims of this study is to investigate the molecular mechanism of adverse association between neuron-degenerative diseases and cancer: 1)explore the pattern of reverse expression and regulation of miRNAs、genes 、pathways and networks in both diseases and propose potential apposing effects and mechanisms that account for the adverse association between them and 2) based on topology of transcriptional regulatory network, we select appropriate molecular targets. Moreover, In different types of cancer cell model with over-expression or knock-down of the selected targets, we further observed the characteristic of cancer cells, such as poliferative ability、tumorigenic potential and so on. Taken together, this study shed some light on the design of broad spectrum anti-cancer drugs in the future.

流行病学研究发现神经退行性疾病患者中存在显著降低的癌症风险，然而目前其内在分子机制尚不清楚。研究综述指出某些miRNA，基因和生物途径在两类疾病中存在反向的表达调控和活性。这些现象提示两类疾病可能存在共同的分子机制，其反向表达调控引发的反向生物效应可能是两类疾病呈负相关性的原因。申请者前期工作中揭示一种典型神经退行性疾病发病不同阶段核心生物途径(JAD,2012)和生物网络（PlosOne,2012）的表达调控变化。在此基础上，本课题拟在转录组水平系统研究神经退行性疾病和癌症的负相关性机制：1）探寻两类疾病中miRNA、基因、生物途径和转录调控网络反向表达调控的模式，并提出其可能引发的反向生物效应和两类疾病呈负相关性的机制。2）依据转录调控网络拓扑结构特征，筛选适当的靶点，研究其过表达或沉默对多种肿瘤细胞凋亡、增殖和成瘤能力等生物学特征的变化。本课题将为设计开发广谱抗癌药物靶点提供新思路。

流行病学研究发现神经退行性疾病患者中存在显著降低的癌症风险，然而目前其内在分子机制尚不清楚。研究综述指出多种基因表达的失调参与神经退行性病变和肿瘤发生的重要细胞生物进程,其中一些基因在两类疾病中存在反向的表达调控和活性。这些现象提示两类疾病可能存在共同的分子机制，其反向表达调控引发的反向生物效应可能是两类疾病呈负相关性的原因。通过对神经退行性疾病和癌症转录组的比较分析，我们确定了两类疾病中反向基因表达调控的模式。另一方面，通过构建小鼠模型，我们还研究了社会精神压力与肿瘤发生和发展的关系，发现社会精神压力可以通过调节肾上腺素的水平从而增强肿瘤的侵袭、转移和干细胞特征。本课题有助于深化对神经系统疾病和肿瘤发病机制和相互关联的认识。