慢性炎症恶性转化是肝癌发生的主要原因之一。白三烯A4水化酶（LTA4H）通过催化生成LTB4参与炎症反应，但其是否参与肝癌发生尚未见报道。我们前期发现肝细胞敲除LTA4H促进小鼠肝癌发生，而巨噬细胞敲除则抑制肝癌发生，此外敲除该基因可明显抑制EGFR表达；有研究证实EGFR通过减轻肝细胞损伤，促进巨噬细胞IL-6表达参与肝癌发生。据此我们推测LTA4H可通过上调EGFR表达，双靶向肝细胞和巨噬细胞参与肝癌发生。本课题计划在此基础上，首先结合临床样本明确肝癌细胞和巨噬细胞LTA4H表达情况及临床意义；其次通过细胞和动物实验明确LTA4H-EGFR轴在肝细胞和巨噬细胞中的生物学功能及在肝癌发生中作用；之后结合多种方法阐明LTA4H调控EGFR表达的分子机制；最后探讨乌苯美司抑制LTA4H阻断肝癌发生的可行性。本研究将加深我们对肝癌发生阶段复杂信号调控的认识，为干预逆转肝癌发生提供新靶点和策略。

Hepatocellular carcinoma ranks fourth in the incidence of cancer in China, malignant transformation of chronic inflammation is one of the main causes of HCC. Leukotriene A4 hydrolase (LTA4H) participates in the inflammatory response through its catalytic product LTB4, however, whether it is actually involved in hepatocarcinogenesis has not been reported. We found that hepatocyte-specific LTA4H knockout could promote hepatocarcinogenesis in mice, while macrophage-specific knockout of LTA4H could inhibit hepatocarcinogenesis. In addition, knockout or knockdown LTA4H could significantly inhibit EGFR expression. It was known that EGFR could protect hepatocytes from damage and promote IL-6 expression in macrophages. Therefore, we speculate that LTA4H can regulate hepatocarcinogenesis by dual-targeting hepatocytes and macrophages via up-regulating EGFR expression. The project plans to: firstly, confirm the expression and clinical significance of LTA4H in HCC cells and macrophages by tissue microarray and mIHC; secondly. clarify the biological function of LTA4H-EGFR axis in hepatocytes and macrophages and its role in hepatocarcinogenesis through cell and animal experiments; later, clarify the molecular mechanism of LTA4H regulating EGFR expression by several experiments including CoIP-MS in vitro and in vivo; finally, investigate the feasibility of Ubenimex to inhibit LTA4H and block the occurrence of HCC. This study will deepen our understanding of the complex signal transduction in the stage of hepatocarcinogenesis, and provide new targets and strategies for intervention of hepatocarcinogenesis.