驱动蛋白家族成员14(KIF14)在髓母细胞瘤中表达上调的分子生物学研究及临床意义

项目名称： 驱动蛋白家族成员14(KIF14)在髓母细胞瘤中表达上调的分子生物学研究及临床意义

项目编号： No.81472373

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： 吴浩强

作者单位： 香港中文大学深圳研究院

项目金额： 68万元

中文摘要： 髓母细胞瘤（MB）是一种高度恶性的中枢神经系统肿瘤，尽管多模式治疗改善了预后，仍有三分之一的患者无法治愈，幸存者也要承受严重的后遗症，因此迫切需要研发新疗法，提高生存率和减少后遗症。我们已证明染色体1q获得在MB中常见。我们发现位于1q上的KIF14基因在MB中表达升高，并且其升高与疾病预后差有显著的相关性。体外实验也证实下调KIF14可抑制MB细胞生长和抑制克隆形成，提示KIF14在MB中具有调节髓母细胞瘤的增生。我们拟深入研究KIF14在髓母细胞瘤中的生物学功能及临床意义，本课题主要分为4个方面:1.分析KIF14对MB的预后价值，探讨KIF14可否作为鉴别MB分子亚型的标志物。2.体外功能及体内实验研究KIF14在MB细胞中的作用。 3.分析KIF14表达对化疗耐药的影响。4.寻找调控KIF14的转录因子。这些结果不仅可以加深我们对MB分子病理机制的理解，而且为研发新型靶向疗法提供依据。

中文关键词： 髓母细胞瘤；运动蛋白14；第1染色体长臂扩增；细胞增殖；化疗耐药

英文摘要： Medulloblastoma (MB) is an aggressive CNS tumors commonly found in children. With recent advances in multimodal treatment, clinical outcome has been improved. Yet, about 1/3 of patients are incurred due to dessimination and chemoresistance. Yet, survivors are suffered from long term neurocognitive deficit and sequelae. Novel target therapy is needed urge. Our research team has demonstrated that gain of chromosome 1q is a chromosomal aberration in medulloblastoma, suggesting the presence of oncogene on chromosome 1q. The questions then are: which gene on chromosome 1q is critical for MB tumorigenesis? What are the biological significances of this gene? Our research team has first identified KIF14, a motor proteins involved in cytokinesis, as a potential oncogene in MB. By gene expression profiling, quantitative RT-PCR, and immunohistochemistry, we show that KIF14 is significantly overexpressed in MB. Upregulation of KIF14 is associated with poor progression-free survival and overall survival. Importantly, in vitro assays demonstrate that knockdown of KIF14 induced cell growth inhibition and suppressed colony formation. These evidence illustrate that KIF14 is not merely a motor protein but it regulates MB growth and development. We are the first to propose to study the clinical significances and biological functions of KIF14 in MB by the following 4 different aspects: 1. examine the value of KIF14 as a prognostic marker for MB. And, by immunohistochemistry and FISH analysis, determine if KIF14 would serve as a potential biomarker for molecular subgroup assignment. 2. By gain- and loss-of-function approaches and varies in vitro assays, establish the roles of KIF14 in cell proliferation, cell cycle progression, colony formation, migration and invasion, tumor sphere formation of MB. The results of these studies would shed a light on the multiply biological functions of KIF14 in MB tumorigenesis. 3. Evaluate the effects of KIF14 expression on the chemosensitivity, providing evidence for improvement of patient management. 4. By sequence analysis, luciferase reporter assay and CHIP assay, identify potential transcription factors regulating KIF14 expression. The results support the multiple mechanisms for KIF4 upregulation. The results of this study would contribute our understanding of MB pathogenesis. In addition, it helps to identify molecular biomarker for prognostic and subgroup affiliation. Importantly, it gains insights into establishment of novel treatment strategy for MB patients and in better patient management.

英文关键词： Medulloblastoma;KIF14;Chromosome 1q gain;Cell proliferation;chemoresistant