Kupffer细胞TREM2受体抑制肝癌发生发展的作用及机制研究

Inflammation mediated by pattern recognition receptor participates in the carcinogenesis and development of hepatocellular carcinoma (HCC). TREM2, a new pattern recognition receptor, mediates immune/inflammatory response. However, the role of TREM2 in HCC remains unknown. Previous studies showed that TREM2 receptor was functionally expressed in Kupffer cells. Our previous study indicated that TREM2 receptor may participate in the carcinogenesis of HCC: 1. TREM2 expression in Kupffer cells was remarkably reduced in tumor tissues of HCC patients and the low expression of TREM2 in Kupffer cells of tumor tissues was correlated with poor prognosis; 2. TREM2 could inhibit cell growth, activation and secretion of inflammation cytokines of Kupffer cells. TREM2 could suppress PI3K and MAPK signaling pathway; 3. TREM2 expression in Kupffer cells was significantly reduced in a chemical-induced HCC mice model. In the present study, we aim to study the effect of TREM2 on tumor behaviors of HCC cells in vitro. We aim to study the role of TREM2 in Kupffer cells in HCC carcinogenesis and development via orthotopic models and DEN-induced HCC model constructed by TREM2 gene knockout mice in vivo. We aim to evaluate prognostic significance of TREM2 in human HCC tissues. Our study will provide new clues to understand the role of pattern recognition receptor in HCC carcinogenesis

模式识别受体介导的炎症反应是影响肝癌发生发展的重要因素。新型模式识别受体TREM2，介导炎症细胞中的免疫识别和炎症反应，但其在肝癌发生、发展中的作用尚不明确。我们前期研究发现Kupffer细胞表达的TREM2可能参与肝癌发生过程：肝癌组织Kupffer细胞中TREM2表达下调，TREM2低表达与预后不良相关；TREM2能够抑制Kupffer细胞增殖、活性及炎性因子分泌，抑制PI3K和MAPK信号途径；化学诱导小鼠发生肝癌导致Kupffer细胞TREM2表达显著降低。我们拟在体外细胞水平研究Kupffer细胞TREM2对肝癌细胞生物学特性的影响；在体内动物水平利用原位移植瘤模型和TREM2基因敲除小鼠构建的化学诱癌模型，探讨Kupffer细胞TREM2信号在肝癌发生、发展中的作用及机制；在临床水平评估Kupffer细胞TREM2的预后价值，为研究模式识别受体在肝癌发生发展中的作用提供新线索。

模式识别受体介导的炎症反应是影响肝癌发生发展的重要因素。新型模式识别受体TREM2，介导炎症细胞中的免疫识别和炎症反应，但其在肝癌发生、发展中的作用尚不明确。本课题研究发现Kupffer细胞表达的TREM2可能参与肝癌发生过程：人肝癌组织Kupffer细胞中TREM2表达下调，TREM2低表达与预后不良相关；体外研究表明TREM2能够抑制Kupffer细胞增殖、活性及炎性因子分泌，抑制PI3K和MAPK信号途径；体内利用TREM2基因敲除小鼠构建的化学诱癌模型证实Kupffer细胞的TREM2表达在小鼠肝癌组织中显著降低；机制研究显示Kupffer细胞TREM2分子与Syk之间存在相互作用。本研究将TREM2和肝癌的病理生理发生过程联系在一起，为研究模式识别受体在肝癌发生发展中的作用提供新线索。