Midkine（MDK）作为一种生长因子在肝癌中异常高表达，血清MDK含量作为肝癌早期诊断指标的灵敏度明显优于甲胎蛋白，但目前机制研究尚不清楚。我们的前期研究发现肝癌细胞中MDK的高表达促进STAT3 Y705位点的磷酸化，后者直接抑制IRF1的转录激活进而抑制肝细胞抗病毒固有免疫应答，同时IRF1促进MDK表达。据此我们提出科学假说：MDK可能通过RTK/STAT3-IRF1-MDK的负反馈回路抑制肝细胞抗病毒固有免疫应答，促进炎症及肝癌发生发展。本课题旨在检验这一科学假说，即拟进一步系统研究MDK在肝细胞抗病毒固有免疫应答中的作用及机制，剖析MDK转录激活的机制，解析MDK调控STAT3磷酸化的机制；利用PDX小鼠模型，探索MDK小分子抑制剂分别在HBV型肝癌和非HBV型肝癌治疗中的作用，为MDK作为新的靶基因应用于病毒性肝癌的靶向及免疫治疗提供新的理论支持。

Midkine (MDK) is a growth factor that has been found to be abnormally up-regulated in hepatocellular carcinoma (HCC), and the sensitivity of serum MDK for HCC diagnosis at early stage is much higher than that of AFP. However, the role and mechanism are still unclear. Our previously study showed that the highly expressed MDK in HCC cell lines promotes STAT3 phosphorylation at tyrosine 705 site (p-STAT3 Y705). STAT3 then directly inhibits the transcriptional activation of IRF1 and thus suppressing the antiviral innate immune response of hepatocytes. Moreover, IRF1 facilitates the expression of MDK. Therefore, we put forward the hypothesis that MDK may inhibit the antiviral innate immune response of hepatocytes through the negative feedback loop of RTK/STAT3-IRF1-MDK, thereby promoting inflammation and development of HCC. On this basis, the present project intends to systematically study the role and mechanism of MDK in antiviral innate immune response of hepatocytes, explore the mechanism of MDK transcriptional activation, and uncover the mechanism of MDK in regulating STAT3 phosphorylation; using a PDX mouse model to investigate the role of MDK small molecule inhibitor in the treatment of HBV-induced HCC versus non-HBV-induced HCC, which may provide a new theoretical support for MDK as a new target for the gene targeting therapy and immunotherapy of virus-induced liver cancer.