【作者】 肖卫华；

【导师】 牛俊奇；

【作者基本信息】 吉林大学 ， 内科学， 2011， 博士

【摘要】 慢性炎症或病毒感染所致Rb基因突变或上游信号缺失是肿瘤的标志之一,导致靶蛋白E2F1的活性异常。临床检测显示,E2F1与肝、肺、胶质瘤、淋巴细胞白血病和生殖系统等多种肿瘤的发生、发展及转移相关。基因敲除或转基因小鼠生命晚期均发生肿瘤,并表现出组织特异性。相对E2F1诱导细胞凋亡的分子机制已有大量研究和认识,E2F1作为肿瘤基因的分子机制仍不清楚,特别是诱导组织特异性肿瘤的分子基础和机制缺乏了解。最近研究表明,E2F1除参与细胞凋亡和细胞周期调控外,在不同细胞中还可分别与NF-κB、PI3K及ERK等主要信号通路有相互作用。据此推测,E2F1促肿瘤作用,特别是其功能的细胞特异性,可能和E2F1与不同细胞中特定信号通路的相互作用有关。为此,我们从E2F1与NF-κB、ERK及PI3K等主要细胞通路在内的相互作用入手,尝试发现和阐述E2F1诱导肿瘤发生和发展的分子基础和机制。项目研究过程中取得以下结果:⑴发现E2F1/NF-κB复合物通过调节EGR-1及细胞生长因子促肿瘤增生及抗凋亡的新机制和信号通路:对其中EGR-1的转录调节的分子机制研究证实,E2F1通过与NF-κB蛋白结合,并利用EGR-1启动子上的NF-κB调控子序列调节EGR-1的基因转录。而EGR-1的持续表达,促进了多种细胞生长因子的表达,这些生长因子包括IGF,PDGF和TNF等是维持肿瘤增生、抗药和扩散等肿瘤特征的重要和必须因素。另外,还发现EGR-1可显著增强IL-8表达,促进肿瘤增生和扩散。部分研究成果已分别发表在Cancer Res. 2009 Mar 15;69(6):2324-31和JBC. 2006;281(15), 10508–10515。⑵发现E2F1/NF-κB复合物抑制ICAM-1表达促肿瘤免疫逃逸新功能:对ICAM-1的转录调控机制研究发现,E2F1可通过与NF-κB结合来抑制ICAM-1的转录,从而达到肿瘤的免疫逃逸。ICAM-1是免疫细胞识别并杀伤靶细胞所必须的表面分子,在肿瘤细胞中往往表达下降从而逃脱免疫杀伤攻击。此部分研究论文正在投稿审稿中。上述研究以前列腺癌为模型,深入、系统的发现和阐述了E2F1作为细胞信号网络的重要节点分子,通过与包括NF-κB在内的其它信号通路对话,参与部分重要基因的转录调控,发挥对肿瘤细胞功能影响的新功能及分子机制。更多还原

【Abstract】 Chronic inflammation or infection-induced mutations or deficiency of pRB is a hallmark of tumors, and that led to disregulation of E2F1. It has been demonstrated from clinical tests that E2F1 is associated with tumorigenesis, development and migrations in a number of tumors including liver, lung, glioma brain, lymphoma and reproduction tumors. Knock-out and transigene mice developed tissue-specific tumors in the later of life. In contrast to the mechanisms of inducing apoptosis by E2F1 have been largely studied., the molecular mechanisms of tumorigenesis of E2F1 are still under investigations. Recent studies showed that, addition to promot cell cycle, E2F1 also crosstalk with some important signaling pathways such as NF-κB, PI3K and ERK in a cell-content dependent fasion. These suggesting that the tumorigenesis role of E2F1 is tissue specific that may involveing signaling crosstalk between E2F1 and major signaling pathways. In this study, we focused on some fundemental mechanisms and functions of E2F1 in tumorigenesis from the view of signaling crosstalks, the results are listed below:(1) Elucidated a novel signaling pathway that E2F1/NF-κB complex transcriptional regulats EGR-1 expression and promotes prostate cancer cell proliferation and antiapoptosisWe showed that E2F1 interacts with NF-κB to form a protein-protein complex and facilities the NF-κB binding site within promoter region of EGR-1 and induces expression of EGR-1. The consistent expression of EGR-1 induces the productions of a panel of growth factors including IGF, PDGF and TNF et al, which promtes cell proliferation and anti-apoptosis in prostate cancers. Futhermore, we also showed that EGR-1 promotes the expression of IL-8 that induces cell growth and metastasis. The results from this studies have published on Cancer Res. 2009 Mar 15;69(6):2324-31 and JBC. 2006;281(15), 10508–10515。(2) The protein–protein complex E2F1/NF-κB suppresses the expression of ICAM-1 that induces immune scapping in prostate cancersIn the study of transcriptional regulation of ICAM-1, we find that E2F1/NF-κB complex is directly binding to the NF-κB site within ICAM-1 promoter and suppresses the expression of ICAM-1 that promote tumor immunescapping in prostate cancer cells. The results in in preperation for publishing on peer-review journals. The studies described in this thesis have elucidated that E2F1/NF-κB crosstalk is a important node in cell signaling pathway, which plays critical roles in tumors through regulating the downstream gene’s expression.更多还原