ASB3基因突变在大肠癌发生发展和转移中的作用及机制研究

项目名称： ASB3基因突变在大肠癌发生发展和转移中的作用及机制研究

项目编号： No.81472256

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： 刘然义

作者单位： 中山大学

项目金额： 70万元

中文摘要： 大肠癌（CRC）的发生发展及转移与一系列基因突变有关。我们通过全外显子组序列分析及临床标本验证发现，CRC组织中ASB3基因的突变频率高达28%，很可能是CRC中一种重要的高频突变基因。初步研究显示ASB3突变可能与CRC分期、病理类型及转移相关，敲低ASB3表达可促进THC8307细胞增殖和迁移，因此研究ASB3突变在CRC发生发展和转移中的作用及其作用机制具有重要意义。本课题拟进一步扩大样本量研究结直肠癌中ASB3突变的临床意义；在细胞和转基因小鼠以及荷瘤动物模型中采用生物芯片、组学分析、诱导型基因表达系统等技术，阐明ASB3突变在结直肠癌发展和转移中发挥的作用及其作用的底物、调控的信号通路和下游靶基因，分析不同ASB3突变位点对其功能的影响。进而为大肠癌的诊断、疗效预测提供可能的分子标志物，为CRC药物研发提供可能的分子靶点。

中文关键词： C08_结；直肠肿瘤；ASB3；基因突变；肿瘤发生发展；肿瘤转移

英文摘要： The occurrence, development and metastasis of colorectal cancer (CRC) is correlated with a series of gene mutation. We previously found mutation frequency of ASB3 gene in CRC is up to about 28% by full exon sequence analysis and clinical sample validation, and ASB3 is likely one of the key high-frequent mutant genes. Preliminary study showed that the ASB3 gene mutation may be associated with staging,pathological type and prognosis of CRC, knocking down ASB3 increased THC8307 cell proliferation and migration, so it is important to study the role that ASB3 mutations play in the progression and metastasis of CRC and the mechanism how ASB3 mutations act. In this project, we will investigate the clinical significance of ASB3 mutation in CRC by a large scale clinical validation; By bio-chip, omics technologies, inducible expression systems, structural biology, and other technoligies, we will further study in cell modles, transgenic mice and xenograft murine models, in order to clarify the rloe of ASB3 mutation in the progression & metastasis of CRC and substrate，pathway and downstream genes regulated by ASB3, to analyze the influence of virant mutant site on the functions of ASB3, to find out the relationship of construction and function of ASB3. Thus will provide a possible molecular biomarker for the diagnosis and treatment effect prediction,a molecular target for the resaerch & development of novel drug of CRC.

英文关键词： colorectal carcinoma;ankyrin repeat and SOCS box-containing 3;gene mutation;tumor development;tumor metastasis