CYPJ抑制炎症应答及结直肠癌发生发展的机制研究

One of the major causes of colorectal cancer (CRC) is the inflammation-tumor transformation in tumor microenvironment. NF-κB signaling pathway and its regulatory proteins play vital roles in inflammation and the progression of CRC. Therefore, the discovery of new regulatory proteins and revealing their roles in CRC might help us understanding more about the occurrence and development of CRC. In our previous study, we identified a novel Cyclophilin member called Cyclophilin J (CYPJ) as a new negative regulator of NF-κB signaling, which can interact with linear ubiquitin chain assembly complex (LUBAC) in NF-κB signaling and its expression is significantly down-regulated in CRC tissues. Besides, in vivo preliminary experiments showed Cypj knockout mice were more susceptible to inflammatory induced CRC model compared to WT counterparts, which indicated its tumor suppressor function. This project planned to explore the function of CYPJ at molecular, cellular, animal and clinical sample levels, aim to illuminate the mechanism of CYPJ in inhibiting LUBAC, reveal the role of CYPJ in the progression of CRC, expect to provide new insight for in-depth understanding the mechanism of inflammatory associated cancer and to provide new potential molecular target for the prevention and treatment of CRC.

结直肠癌(CRC)发生的一大关键因素是肿瘤微环境中的炎-癌转化。其中NF-κB信号通路是炎症调控的关键信号通路，若干NF-κB通路蛋白及其调控蛋白在CRC发生发展中发挥重要作用。发现新的NF-κB调控蛋白，揭示其在CRC中的肿瘤生物学功能，对于深入认识CRC的发生发展具有重要意义。我们在前期研究中筛选到一个新的NF-κB负调控蛋白亲环素蛋白J(CYPJ)，它能结合NF-κB通路中的线性泛素链组装复合物(LUBAC)并在结直肠癌组织中显著下调表达。在小鼠炎性肠癌模型中，Cypj敲除鼠的癌变率明显高于野生组，提示CYPJ具有重要的抑癌功能。本项目拟从分子、细胞、动物、临床样品等多个层面对CYPJ的功能进行深入探讨，旨在阐明CYPJ通过负调控LUBAC抑制NF-κB信号通路的分子机制，揭示CYPJ在CRC发生发展中的功能，为深入认识炎-癌转化机制提供新的思路，为CRC的防治提供新的分子靶标。

结直肠癌（colorectal cancer, CRC）是世界范围内最常见的恶性肿瘤之一，我国CRC的发病率和死亡率均处于持续上升趋势，发病率已居恶性肿瘤第二位，死亡率第四位，防治工作依然任重而道远。CRC发生发展是一个涉及多基因多步骤演变的复杂过程，其中，微环境中的慢性炎症是其癌变的一个重要诱因。NF-κB信号通路作为炎症调控的关键信号通路，已被证实在包括CRC在内的多种肿瘤中持续过度活化，加速了肿瘤的恶化进程。从炎-癌转化的角度，发现新的NF-κB调控蛋白，揭示其在CRC中的生物学功能，对于深入认识CRC的发生机制和CRC的防治具有重要意义。本项目从分子、细胞、基因敲除小鼠、转基因小鼠、临床样本等多个层面对包括NF-κB通路负调控蛋白CYPJ和CRC增殖相关蛋白DKC1展开了深入探讨，揭示了CYPJ在炎症调控/炎癌转化中的分子机制以及DKC1促进肿瘤细胞生长的分子机理，为深入理解CRC的发生和发展提供新的线索。同时，结合临床样品中CYPJ、DKC1的异常表达情况及预后分析结果，提示他们均具有开发成CRC新靶标或患者预后标志物的潜在转化价值。此外，通过对吩噻嗪类化合物“三氟拉嗪”（Trifluoperazine, TFP）的抗病毒机制研究，发现TFP具有显著的抑制RNA病毒和DNA病毒复制的作用，具有开发成广谱抗病毒药物的潜能。署名本项目的2篇SCI论文分别发表在Frontiers in Microbiology和Advanced Science；培养了1名博士生及1名博士后。