幽门螺杆菌促进模式识别受体NLRP3表达介导炎癌转化的调控机制

Mechanism for chronic inflammation malignant transformation mediated by Helicobacter pylori (H. pylori) is a significant unsolved scientific problem. NLRP3, as an important inflammasome component, has crucial roles in initiating inflammation. However，the potential roles of NLRP3 in this process is unclear. Applicants found that NLRP3 expression is markedly upregulated and played key roles in the process of malignant transformation mediated by H. pylori infection. On the base of the above finding , this project intends to address the following questions: (1) Mechanisms through which H. pylori infection increases NLRP3 expression. （2）How does NLRP3 promote malignant transformation？Combining scientific frontier and previous studies, the contents of this project can be summarized as the following: (1) validating the hypothesis that H. pylori induce NLRP3 expression through transcriptional factor (Sp1), histone demethylase (PHF8) and miRNA (miR-22) both in gastric epithelial and infiltrated macrophage. Upregulated NLRP3 promoted inflammation malignant transformation through inflammsome-dependent and –independent functions, which triggered the cross-talk between gastric epithelial cells and macrophage.（2）Confirming the relationship between NLRP3 (including its target genes) and malignant transformation, and the role of this molecule in the clinical prognosis of patients with gastric cancer to evaluate the function of NLRP3 in the H. pylori induced gastric carcinogenesis. This will suggests NLRP3 as a potential target for the intervention of GC.

幽门螺杆菌介导的炎性反应与恶性转化是重要研究领域，申请者发现NLRP3在其中蕴含功能。据此，本项目聚焦研究目标：幽门螺杆菌促进模式识别受体NLRP3表达介导炎癌转化的调控机制；回答科学问题：（1）幽门螺杆菌感染通过何种机制促进NLRP3表达？（2）幽门螺杆菌诱导表达的NLRP3通过何种机制介导炎癌转化？综合科学前沿和前期研究，凝练研究内容：从分子细胞、实验动物和人体病理组织三个层面，以“转录因子（Sp1）— 组蛋白修饰（PHF8）— miRNA修饰（miR-22）”为切入点，从转录（Sp1/PHF8）和转录后（miR-22）两个水平解析幽门螺杆菌促进NLRP3表达的机制，从炎性小体依赖性（释放IL-1β）和炎性小体非依赖性（NLRP3核转录调控）两个方面解析由幽门螺杆菌诱导表达的NLRP3介导炎癌转化的机制。旨在为靶向NLRP3为调控节点的幽门螺杆菌相关炎癌转化防控提供理论依据

幽门螺杆菌是胃粘膜组织恶性转化的病原学因素，解析幽门螺杆菌感染介导胃粘膜组织恶性转化调控机制是重要的科学问题。本研究结果显示：NLRP3在慢性胃炎向胃恶性转化过程中逐渐升高，且其高表达促进胃上皮细胞异常增殖；NLRP3通过炎性小体依赖性和非依赖性两种方式促进细胞异常增殖；NLRP3在核内可以转录激活CCND1的表达；miR-22 可以直接靶向NLRP3降解其mRNA；当发生幽门螺杆菌感染时，组成性高表达的miR-22明显被抑制，对NLRP3的抑制减弱，所以NLRP3的表达明显上调，此时NLRP3炎性小体发生聚集及激活，导致巨噬细胞产生大量的IL-1β，IL-1β可以进一步抑制miR-22的表达从而反馈性的促进巨噬细胞中NLRP3炎性小体激活，促进胃上皮细胞的异常增殖。此外，在胃粘膜上皮细胞中，NLRP3可以通过直接激活CCND1的转录进一步促进上皮细胞的异常增殖。因此，本研究证实了幽门螺杆菌通过调控miR-22促进NLRP3表达，miR-22通过抑制巨噬细胞和胃上皮细胞中NLRP3的表达维持了胃部微环境的稳态，miR-22是阻断幽门螺杆菌感染炎症诱发胃恶性转化的重要靶点，因此通过miR-22调节NLRP3的表达可能在胃恶性转化防治过程中具有重要意义。本研究丰富了幽门螺杆菌感染导致胃黏膜恶性转化的机制，为基于miR-22调节NLRP3机制防控幽门螺杆菌相关恶性转化提供了理论基础。