HBV感染引起的病毒持续复制和HBx蛋白的表达是乙型肝炎-肝硬化-肝癌动态进展的主要原因，但确切机制不明。近年来研究表明，CCL2/CCR2在慢性炎症、肿瘤生长和转移、免疫抑制及免疫逃逸等过程中发挥重要功能。申请者前期研究发现CCL2/CCR2介导了微环境中肝癌细胞、巨噬细胞、CD8+T细胞交互作用，对于肝癌的生长和转移至关重要。本项目以乙型肝炎-肝硬化-肝癌为主要模型，利用人群样本和化学诱导的HBx/CCR2转基因小鼠肝癌模型，研究CCL2/CCR2 信号及相关炎症细胞在 HBV 感染导致慢性肝炎恶性转化不同病程阶段的动态变化，探讨CCL2/CCR2 在肝炎恶性转化过程中的功能和网络调控机制，进一步评估CCL2/CCR2作为乙型肝炎恶性转化预防和化学干预靶标的可行性。该研究不仅深化了对慢性肝炎恶性转化的分子机制的认识，也为发展新型的肝癌早期干预、预后预测分子靶标提供研究基础。

Persistent viral replication and expression of hepatitis B virus X protein caused by HBV infection is the main reason for the development of hepatitis B, liver cirrhosis, and liver cancer, but the exact mechanism of dynamic disease is unclear. Recent studies show that, CCL2/CCR2 axis contributes great effects in chronic inflammation, tumor growth and metastasis, immune suppression and immune evasion. Our preliminary data suggested that CCL2/CCR2 signaling mediated the mutual interaction among tumor cells, macrophages, CD8+T cells in the tumor microenvironment, and plays vital important role for the growth and metastasis of hepatocellular carcinoma (HCC). For our current proposal, we will focus on the dynamic progression from hepatitis B, liver cirrhosis to HCC using clinical samples and CCL4/ ethanol induced liver cancer model with HBx transgenic mice (CCR2+/+ and CCR2-/-). We will evaluate the functional role of CCL2/CCR2 axis and related inflammatory cells in the process of malignant transformation of hepatitis, find out the exact mechanism of network regulation and further determine application value of CCL2/CCR2 as the biomarker for clinical diagnosis and prognosis prediction in patients with HCC. Finally, by inhibiting the activation of CCL2/CCR2 signaling, we will evaluate the feasibility of CCL2/CCR2 as the intervention target to block the malignant transformation of hepatitis B. This study not only deepens the understanding of the molecular mechanisms of malignant transformation of chronic hepatitis, but also indicates CCL2/CCR2 could be a putative target for HCC prevention and treatment.