膜联蛋白A4对NF-κB的正反馈调控作用及其对胆囊癌生物学行为的影响

项目名称： 膜联蛋白A4对NF-κB的正反馈调控作用及其对胆囊癌生物学行为的影响

项目编号： No.81201941

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学2

项目作者： 姚厚山

作者单位： 中国人民解放军第二军医大学

项目金额： 23万元

中文摘要： NF-κB活化及其入核调控靶基因转录的机制仍未阐明，ANXA4可能在这一过程中起重要作用；而ANXA4基因存在TP53和NF-κB的结合位点并可被TP53调控表达，结合TP53和NF-κB相互竞争的关系，我们认为在TP53突变的细胞中ANXA4可能受NF-κB调控表达。尽管ANXA4在肿瘤发生、发展过程中的生物学功能仍未可知，课题组前期研究显示ANXA4在存在TP53突变和NF-κB异常激活的胆囊癌中高表达。本项目拟从体外细胞增殖、凋亡、迁移和侵袭力检测，体内成瘤和治疗实验二个层面系统的诠释ANXA4对胆囊癌细胞生物学行为的影响；并在体外细胞分析、体内治疗实验和人组织标本验证三个层面检测ANXA4对NF-κB的正反馈调控作用，初步探索ANXA4对胆囊癌细胞增殖、转移的影响及其细胞内信号转导机制，并进一步阐明NF-κB活化及其入核调控靶基因转录的机制，ANXA4有望成为胆囊癌的治疗靶点。

中文关键词： 胆囊癌；膜联蛋白-A4；NF-κB；p65；正反馈调节

英文摘要： The activation of NF-κB and its interaction with chromatin in regulating gene expression programs is an unanswered question and need to be intense investigated, ANXA4 may play an important part in this process. ANXA4 gene has binding motifs for TP53 and NF-κB, and it could be regulated by TP53. While ANXA4 gene could be regulated by NF-κB in cells with TP53 mutation in our opinion according to the competition relationship between TP53 and NF-κB. Although the role of ANXA4 in the development and progression of cancer is unclear, it might be involved in the tumorigenesis and lymph node metastasis of primary gallbladder cancer (PGC) which has TP53 mutation and NF-κB activation according to our previous research. The aim of the present study is to analyze the role of ANXA4 on proliferation and invasion of PGC and its interaction with NF-κB, by which the regulation mechanism of NF-κB on proliferation and invasion of PGC will be illuminated. The effect of ANXA4 on proliferation and invasion of GBC-SD and NOZ cells will be detected in vivo and vitro to determine the biological function of ANXA4 in the development and progression of PGC; the effect of ANXA4 on transcriptional activity of NF-κB and the effect of NF-κB on expression of ANXA4 will be detected in vivo, vitro and clinical analysis to determine the positive f

英文关键词： gallbladder cancer；annexin A4；NF-κB；p65；feedback circuit