TRAF2促进肝脏炎症癌变过程的作用机制研究

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide, and no effective drugs for the treatment now. So, find new drug targets still important for its therapy. It is well established now that chronic and persistent inflammation contributes to cancer development. One of the major insights got from investigated the relationships between inflammation and cancer is that most cancers are preventable if you target in the inflammation stage. Prevention is a much better and more economical way to fight cancer. So find targets that could work on prevent inflammation to tumorigenesis is a really hot research area nowadays. Nuclear factor-κB (NF-κB) is a transcriptional regulator of genes involved in immunity, inflammatory response, cell fate, and function. Recent attention has focused on the pathophysiological role of NF-κB link the inflammation and tumorigenesis in liver cancer. The Inflammation-Fibrosis-Cancer Axis showed the ability of NF-κB to regulate the interplay between immune, fibrogenic, and oncogenic mediators and the potential for this complexity to bear fruit in the form of highly specific therapeutics. TNF receptor-associated factor-2（TRAF2）is the key molecular to regulate NFκB pathway activation, and participate the process of infection and carcinogenesis. Based on the reference and work we did before, we found that siTRAF2 could activate NF-κB, also TRAF2 is synthetic lethal with p53, and could disturb cell cycle proteins as well. So we think that TRAF2 may play important roles to link liver inflammation and tumorigenesis in HCC. So we designed in vivo and in vitro experiments to validate our hypothesis, investigated the relationship of TRAF2 with NF-κB and p53 pathways. Hence, we anticipate that TRAF2 is a good target for HCC treatment, and development of drugs reducing endogenous TRAF2 level might be important in the treatment of inflammation-related hepatocarcinoma.

寻找新靶点是肝癌治疗关键性问题，近年多项权威研究发现肝脏炎症和癌症关系密切，对于炎性反应的调控可以抑制肿瘤的发生发展，所以在这个过程中的恶变因素成为新的研究热点。NF-κB是联系炎症和肿瘤发生最为重要的通路之一，肿瘤坏死因子受体结合因子2(TRAF2)是NF-κB通路中的关键调控分子。我们此前大规模RNAi文库筛选，发现TRAF2在p53变异的情况下更易致肿瘤细胞的死亡，其机制可能和TRAF2对NF-κB的调控相关，我们也曾报道TRAF2在调控肿瘤细胞NF-κB通路和细胞周期中有重要作用, 但其作用机制尚缺乏深入了解。本课题追踪TRAF2调控进展及炎症和肿瘤关系研究的前沿热点问题，延续之前工作基础，通过调控肝脏实质和间质细胞TRAF2的表达及DEN诱导的肝癌模型及其裸鼠移植瘤模型，探讨TRAF2参与NF-κB、p53信号调控的关系，从细胞和动物水平明确TRAF2参与肝脏炎症癌变过程的作用。

寻找新靶点是肝癌治疗关键性问题，近年多项权威研究发现肝脏炎症和癌症关系密切，对于炎性反应的调控可以抑制肿瘤的发生发展，所以在这个过程中的恶变因素成为新的研究热点。NF-κ B 是联系炎症和肿瘤发生最为重要的通路之一，肿瘤坏死因子受体结合因子2(TRAF2)是NF-κ B 通路中的关键调控分子。我们此前大规模RNAi 文库筛选，发现TRAF2 在p53 变异的情况下更易致肿瘤细胞的死亡，其机制可能和TRAF2 对NF-κ B 的调控相关， 我们也曾报道TRAF2 在调控肿瘤细胞NF-κ B 通路和细胞周期中有重要作用, 但其作用机制尚缺乏深入了解。本课题组首先通过临床研究发现TRAF2的高表达与重型肝炎及肝癌的发生相关；接着我们构建了一系列调控TRAF2表达的细胞株，从细胞水平观察TRAF2表达的改变对肝癌细胞的影响，并利用实时细胞监测技术（RTCA）发现沉默TRAF2之后，p53突变型肿瘤细胞的死亡率高于p53野生型肿瘤细胞；提示TRAF2可能和p53突变型有合成致死作用。另外，我们发现小分子化合物0404能通过激活p53通路有效抑制肿瘤生长，而0404亦能抑制肝癌细胞中TRAF2的表达，这更说明了TRAF2能通过调控p53通路来影响肿瘤的生长。而在重型肝炎中，我们发现TRAF2能介导NF-κ B 通路来调控炎症的发生，进一步研究发现紫草素、白藜芦醇、没食子儿茶素没食子酸酯（EGCG）等药物都能通过抑制相关细胞中的TRAF2-NF-κ B 通路来减轻炎症的发生。TRAF2是一个重要的信号转导分子，为了进一步阐明它在炎症、肿瘤发生的信号通路中的作用机制，我们利用串联亲和纯化技术（TAP）来寻找TRAF2关键的作用底物，经过验证后，明确了一系列新的TRAF2重要的底物分子，如BTK、DCAF7等。通过研究证实了TRAF2在肝癌发生、发展中的作用，为肝癌的诊治提供了新的靶位。