既往研究证实IL-22与正常细胞增殖相关；S1P可经其受体S1PR1持续活化STAT3促进肿瘤细胞增殖。我们发现：(1)胰腺癌组织中高表达的IL-22与癌细胞增殖相关。(2)在胰腺癌中IL-22介导了S1P活化酶（SphK1）的表达。(3)IL-22与S1P在胰腺癌中的表达共同增高，呈正相关。我们推测：IL-22通过SphK1促进S1P的生成，后者激活胰腺癌细胞膜上的S1PR1，从而持续活化STAT3通路促进癌细胞增殖。拟研究(1)胰腺癌微环境中IL-22+细胞的活化机制；(2)IL-22通过SphK1促进S1P生成并激活S1PR1， 经STAT3通路促进胰腺癌细胞增殖的机制，并在IL-22基因敲除小鼠模型进行反向验证。本研究有望阐明胰腺癌微环境对IL-22+细胞的活化及IL-22通过促进S1P生成、激活S1PR1持续活化STAT3导致胰腺癌细胞增殖的分子机制，为胰腺癌治疗提供新思路。

Previous studies have confirmed the correlation between IL-22 and the proliferation of normal cells; S1P can promote the proliferation of tumor cells by continuous activation of STAT3 via its receptor S1PR1. We found that: (1) IL-22 highly expressed by T cells in pancreatic tissue was related with proliferation of cancer cells. (2) Expression of the S1P activating enzyme (SphK1)was mediated by IL-22 in pancreatic carcinoma. (3) Expression IL-22 and S1P in pancreatic carcinoma increased simutaneouly, which had a positive correlation. We speculate: IL-22 promotes the production of S1P via SphK1; S1P binds to its receptor- - S1PR1, then persistently activates STAT3 pathway which finally lead to the proliferation of cancer cell. We are planning to investigate: (1) The activation mechanism of IL-22 in the pancreatic carcinoma microenvironment; (2) To elucidate the mechanism that IL-22 promotes the production of S1P via SphK1; S1P binds to its receptor- - S1PR1, then persistently activates STAT3 pathway which finally lead to the proliferation of cancer cell; Reverse validate the mechanism in the IL-22 knock-out mice model. The study is expected to clarify the molecular mechanisms of activation of IL-22 + cells in the pancreatic carcinoma microenvironment and IL-22 promote the proliferation of pancreatic carcinoma cells by upregulating S1PR1, and provide new ideas for the treatment of pancreatic carcinoma.

本课题顺利按时完成了相关的科研计划任务，在胰腺癌患者血液、肿瘤组织和正常对照中，采用免疫组织化学、Western blot、流式细胞等技术检测出IL-22高表达于胰腺癌患者，且与临床分期分级密切相关。体外实验证明了高表达的IL-22能通过SPHK1催化S1P，经S1PR1和STAT3促进胰腺癌增殖的分子机制；同时发现miR-506与SPHK1mRNA中的保守序列相匹配，双荧光素酶报告实验、WB、免疫组化等实验证明miR-506可直接调控SPHK1mRNA，下调SPHK1蛋白表达，活化Akt/NF-κB信号通路，降低胰腺癌对化疗药物的抵抗，抑制胰腺癌细胞增殖并促进其凋亡。通过相关的实验成功培养了硕士生2名，博士生1名，发表SCI相关论文5篇，获得国家重点研发计划1项（项目编号2017YFC1308600），申请国家专利1项。