食管鳞癌中Survivin对NF-κB信号通路的调控机制研究

Kazakhs esophageal cancer (EC) is the most high incidence and mortality rate disease in Xinjiang. Unfortunately, the molecular mechanisms that related with the constant expression of SURVIVIN，and in which that NIK/NFkB signal pathway might be up regulated by SURVIVIN in the tumorigenesis is still unclear. Tumorigenes is the process that many factors, including chemical and biological carcinogenic factors，might interfere the apoptosis and cell cycle through up regulating the expression of SURVIVIN; several transcriptions factors, such as NFkB, might affect the expression of SURVIVIN. But these data still cannot give the answer for our questions. Our results indicated that survivin has the capability to keep the activities through interacting the expressions of Ikkα/Ikkβ, which indicated that there might have a SURVIVIN-NIK/NFkB up stimulation in tumor cell. Thus, we are planning to complete the study of this SURVIVIN-NFkB up stimulation in ECA109 cells; to promote the expression of SURVIVIN or NFkB with their cDNA expression constructs in cells to determine the expression of NFkB will be induced by over-expressed SURVIVIN. To define this circuit and the influences on the cell apoptosis and cell cycle at a certain time point, and evaluate the consequences with the individual gene knocked down by RNAi. It will help us to understand the mechanisms that SURVIVIN participated process of carcinogenesis.

新疆哈萨克族食管癌是地区特高发疾病之一，但对其癌组织中的SURVIVIN持续高表达以及其中Survivin可能正向调控NIK/NFkB信号系统的分子机制的研究尚属空白。肿瘤发生系通过包括生物、化学致癌物等多种因素逐步启动SURVIVIN基因的表达、参与细胞凋亡和周期的调控；NFκB等多种转录调控因子影响SURVIVIN的表达。我们的前期结果显示，Survivin对NIK/NFκB信号通路中的Ikkα/Ikkβ有正向调控作用并以此上调NFκB p65的磷酸化水平，藉此增高的NFkB活性，这可能是持续诱导SURVIVIN表达原因之一。本项目拟完善SURVIVIN对NIK/NFκB信号通路正向调控机制的研究；明确Survivin-NIK/NFκB正向调控机制对SURVIVIN本身表达的影响和对细胞凋亡、周期的影响。研究结果为理解SURVIVIN的持续高表达模式对食管鳞癌发生发展的重要性提供依据。

新疆哈萨克族食管癌是地区特高发疾病之一，但对其癌组织中的SURVIVIN持续高表达以及其中Survivin可能正向调控NIK/NFkB信号系统的分子机制的研究尚属空白。本项目拟完善SURVIVIN对NIK/NFκB信号通路正向调控机制的研究；明确Survivin-NIK/NFκB正向调控机制对SURVIVIN本身表达的影响和对细胞凋亡、周期的影响。我们的结果证实Survivin通过Ikkβ正向调控NFkB的活性；初步确定在Ikkβ启动子区Survivin干预的区域（-700--1），Survivin可能间接通过转录调控因子干预Ikkβ的表达。这些结果为我们在肿瘤细胞中确认Svv-Ikkβ-NFkB-Svv循环调控Survivin的表达，解释Survivin在肿瘤细胞中逐步表达增高的生物学现象，为肿瘤细胞的高强生存能力和现象提供理论机制。