Stat5调控NLRP3诱导细胞焦亡招募MDSC介导胰腺炎癌转化的机制

本项目前期在国家自然科学基金委重大研究计划（91229117）的资助下，通过分析胰腺炎症、癌旁及癌症标本的转录组学数据，运用原创的动态网络标志物（DNB）方法，发现胰腺炎症进程中存在炎癌转化的关键节点，并筛选出重要的上调基因Stat5。进一步实验表明，Stat5通过上调炎性小体NLRP3表达，诱导胰腺细胞焦亡和促炎症因子释放，增加微环境中髓样抑制性细胞（MDSC）的招募。而MDSC浸润又与炎癌转化密切相关。但Stat5如何促进胰腺炎癌转化机制不清。基于前期结果，我们提出科学假说：Stat5通过上调NLRP3，诱导细胞焦亡，引发促炎症效应，招募MDSC介导胰腺炎癌恶性转化。本课题将通过分子、细胞生物学以及模式动物研究，阐明Stat5如何诱导细胞焦亡，以及分泌炎性因子招募MDSC的机制，最终促进胰腺炎癌转化。本项目的实施为实现临床上胰腺炎癌转化的早期预防和个体化治疗提供理论基础和科学依据。

Based on the National Natural Science Foundation of China (NSFC) program of Regulatory networks and molecular mechanisms of malignant transformation of uncontrolled inflammation, this program have used the dynamic network marker DNB method to found the key node gene Stat5, through detecting and analyzing the transcriptomics data of pancreatic inflammatory, adjacent tissues and cancer tissues. Interference with Stat5 can inhibit the pancreatic cell pyroptosis、related inflammatory factors release and the recruitment of myeloid-derived suppressor cell (MDSC). The invasion of MDSC is closely related to the pancreatitis malignancy transformation. Based on the sequencing results of clinical specimens and in vitro studies, we put forward the scientific hypothesis that Stat5 can upregulate NLRP3 level to induce cell pyroptosis and promote inflammation, and then recruit MDSC to mediate malignant transformation of pancreatic cancer. Based on the above results and the scientific hypothesis, we next plan to investigate the molecular mechanism of Stat5 induce pyroptosis and proinflammatory effects, thus affect the recruitment of MDSC by molecular and cell biology experiments and spontaneous cancer mice model and Stat5 conditional knockout mice model, and clinical verification. The study of this project will provide theoretical and scientific basis for the early prevention and individualized treatment of the pancreatitis malignancy transformation.