HBV感染引发持续性炎症是原发性肝癌发生发展的重要原因，其机理有待进一步明确。我们的前期研究证实原发性肝癌组织中TNFAIP1表达显著低于癌旁组织且其表达与肝癌分级负相关，表明TNFAIP1在HBV诱导的原发性肝癌中有重要作用。由于CREB磷酸化和NF-kB磷酸化增强HBV复制；而我们发现TNFAIP1抑制CREB磷酸化，通过降解CK2影响NF-kB磷酸化；因此提出TNFAIP1能抑制HBV复制。鉴于HBV关键蛋白HBx和HBc促进CREB转录活性，CREB负调控TNFAIP1；TNFAIP1和HBV间存在反馈调控。本项目拟进一步收集临床标本研究TNFAIP1与HBV持续感染进程之间的关联性；探明TNFAIP1在HBV激活NF-kB信号通路中的分子机制；并用HBV转基因小鼠模型观察干预TNFAIP1能否影响HBV复制、阻断HBV诱导的原发性肝癌进程。这将为临床诊断和干预提供一个新的思路。

Primary Liver Cancer (PLC) is mainly related to the persistent inflammation induced by Hepatitis B Virus (HBV) infection, the mechanism still remains unclear. Our previous studies demonstrated that the expression of TNFAIP1 was obviously decreased in PLC tissues compared to those paracancerous tissues, and showed a inverse correlation with pathological grading; this implies the important role of TNFAIP1 in the HBV-induced PLC. Since the phosphorylation of CREB or NF-kB enhances the HBV replication; and we found TNFAIP1 could inhibit the phosphorylation of cAMP-Response Element Binding Protein (CREB), and degrade CK2 to downregulate the phosphorylation of NFkB; we prospect that TNFAIP1 may inhibit the HBV replication. A feedback regulation cycle exists if considering that TNFAIP1 is negatively regulated by CREB, whose transcription activity could be increased by HBx and HBc. In this project, we plan to verify the correlationship between TNFAIP1 expression and the progress of HBV related PLC using more clinical samples; clarify the molecular mechanisms how TNFAIP1 functions in the process of NF-kB activation by HBV; and check if TNFAIP1 intervention could block the progress of HBV-induced PLC using HBV transgenic mouse model. This may lead to a new way for diagnosis and clinical intervention of PLC.