ATF3负向调控炎症和肿瘤进展的机制及其抗肿瘤治疗作用研究

Cancer is the leading cause of total disease burden in China. Controlling cancer progression is key to making inroads into combating this disease. We have shown that activating transcription factor (ATF) 3, an early response gene that functions in cell death, survival and proliferation, also suppresses metastases of bladder cancer cells and its reduced expression is associated with bladder and colorectal cancer progression (Yuan et al, 2013 Cancer Research). However, the molecular mechanisms underlying ATF3 function in cell fate determination remain to be determined. ATF3 is a member of a family of basic-region leucine zipper (bZip) transcription factors, which, as a homodimer or heterodimer with other bZip proteins, can function as a transcriptional activator or repressor. In our more recent Nature Immunology（2014）paper, ATF3 suppressed inflammatory in additional of TLRs, demonstrated that high-density lipoprotein（HDL）mediates anti-inflammatory reprogramming of macrophages via ATF3. TLRs identified ATF3 as a negative regulator of TLR signalling, likely acting via nuclear factor kB (NF-kB). Since TLR signalling can both promote and eliminate developing tumours and sculpt tumour immunogenicity, it is important to better understand how this is balanced and what role ATF3 plays in this process. ATF3 is also a stress-activated regulator of p53 protein function and stabilises and augments its functions. Accordingly, our central goal is to examine how ATF3 suppresses tumourigenesis, both via negative regulation of TLR signalling in inflammation-induced cancer and during tumour progression。Our grant is based on data current published cancer research and more recent Nature Immunology paper, ATF3 suppressed inflammatory. it was described that decreased ATF3 was associated with bladder cancer progression and reduced survival of patients with bladder cancer, Mechanistic studies revealed that ATF3 suppresses metastasis of bladder cancer through regulating gelsolin (GSN)-mediated remodeling of the actin cytoskeleton. In our unpublished data, ATF3 expression is also lost in dysplastic epithelial cells of colorectal cancer samples from human patients as well as in AOM/DSS treatment in mouse models. The reduction in expression in ATF3 associated with bladder and colorectal progression suggests that chromatin remodelling and epigenetic silencing may be playing a role in regulating ATF3 expression. Importantly, new preliminary data strongly supports us will provide proof-of-principle supporting data for ATF3 can be re-expressed and suppresses metastasis of cancer through HDAC inhibitor pracinostat. We hypothesise that ATF3 not only acts as a critical negative regulator in TLR signalling, but can also suppress the metastatic phenotype such that modulation of its activity will affect the inflammatory response and tumour progression. We propose a series of basic and translational studies to test this novel hypothesis。

恶性肿瘤是危害人类健康并致死的最大危险因素，治疗的关键是控制其进展。本课题基于我们当前发表的Cancer Research等论文，即早期应答基因-转录激活因子3（ATF3）在肿瘤发生发展中发挥重要作用，可抑制肿瘤转移。最近我们与德国学者联合发表Nature Immunology(2014)论文发现ATF3可抑制TLR受体引起的促炎细胞因子表达，在抗炎症中起关键作用。我们前期研究结果显示ATF3表达减少与结肠癌进展密切相关，而且经组蛋白去乙酰化酶抑制剂pracinostat处理后ATF3重新表达并抑制肿瘤细胞转移。这提示ATF3可能参与炎症性肿瘤的发生发展并可能是潜在治疗靶点。本项目拟进一步深入研究ATF3在炎症介导肿瘤发生中的作用，利用基因敲除小鼠模型研究ATF3抑制肿瘤进展的具体机制，并探讨ATF3调控的临床治疗价值。该项目将为探索炎症及肿瘤进展的分子机制和开发新治疗靶点提供实验基础。

恶性肿瘤是危害人类健康并致死的最大危险因素，治疗的关键是控制其进展。本课题基于我们以前发表的Cancer Research 等论文，即早期应答基因-转录激活因子ATF3在肿瘤发生发展中发挥重要作用。最近我们发现具有调节分子特征的转录因子ATF3的过表达与结肠直肠癌的致病性发展相关(2017年发表在Oncotarget杂志上)。 表观调控因子EZH2对肿瘤的治疗及免疫稳态的调控也是肿瘤及其他疾病的发生发展的关键因素，因此我们开展此方向的研究，发表了二篇文章（2015年Clin Exp Pharmacol Physiol 和2017年EMBO Rep.），在这一表观调控信号通路的基础上，我们又探究组蛋白去乙酰化酶（HDAC）抑制剂调控ATF3 抗炎症新机理（投稿中），转录因子PLZF在表观水平上调控炎症的新机理发表在PNAS杂志上（2015）。组蛋白乙酰基转移酶HAT1通过调控转录因子PLZF调节了NF-kB反应（Nature Communications）(2015). 除了表观调控，炎症相关的信号通路外调控，离不开肿瘤微环境，我们又探索肿瘤微环境中的PD-L1和浸润免疫细胞等新的生物标志物对肿瘤免疫的影响和机制又发表了二篇文章（2018年Oncoimmunology 和2017年J Transl Med）， 该项目将为探索炎症及肿瘤进展的分子机制和开发新治疗靶点提供实验基础。