接头蛋白DAP12通过调控糖酵解途径抑制肝癌发生发展的作用及机制研究

The Warburg effect participates in carcinogenesis and development of tumors, of which the mechanisms remains unknown. Adaptor protein DAP12 could transduce the signals in cells. However, the roles of DAP12 in tumors especially in hepatocellular carcinoma (HCC) remains unknown. Our previous study indicated that DAP12 may be involved in carcinogenesis of HCC via regulating glycolysis and thus suppressing the Warburg effect: 1. DAP12 could significantly inhibit glycolysis; 2. DAP12 located mainly in the cytoplasm and mitochondria; 3. DAP12 suppressed glycolysis and mitochondrial respiratory function in vitro; 4. DAP12 could interact with PKM2 and DAP12 could inhibit PKM2 expression at protein level. In the present study, we aim to study the effect of DAP12 on glycolysis of HCC cells in vitro. We aim to study at the influence of DAP12 on Warburg effect in vitro. We aim to study the role of DAP12 in HCC carcinogenesis and development via orthotopic HCC models and DEN-induced HCC model constructed by DAP12 gene knockout mice in vivo. We aim to evaluate correlation between DAP12 expression and glycolysis as well as the clinical significance in human HCC tissues. Our study will provide new clues to understand the novel role of adaptor protein in the Warburg effect and HCC carcinogenesis.

Warburg效应是参与肿瘤发生、发展的重要因素，其机制研究一直是肿瘤领域的热点。接头蛋白DAP12能够介导细胞内信号传导，但其在肿瘤尤其肝癌发生、发展中的作用尚未明确。我们前期研究发现肝脏表达的DAP12可能通过丙酮酸激酶M2（PKM2）信号调控糖酵解途径对抗Warburg效应从而抑制肝癌发生、发展：DAP12能够显著抑制糖酵解途径；DAP12在肝癌细胞胞质和线粒体中均有表达；细胞中DAP12能够抑制糖酵解及线粒体氧化呼吸功能；DAP12与PKM2之间存在相互作用，DAP12能够抑制PKM2在蛋白水平的表达。我们拟在体外细胞水平研究DAP12对肝癌细胞Warburg效应的影响；在体内动物水平利用原位移植瘤及化学诱癌模型，探讨DAP12信号在肝癌发生、发展中的作用及机制；在临床水平评估DAP12与糖酵解的相关性，为研究接头蛋白通过调控Warburg效应抑制肝癌发生发展的作用提供新线索。

Warburg效应是参与肿瘤发生、发展的重要因素，其机制研究一直是肿瘤领域的热点。接头蛋白DAP12能够介导细胞内信号传导，但其在肿瘤尤其肝癌发生、发展中的作用尚未明确。本课题组研究发现：DAP12基因缺失小鼠肝癌发生和转移明显增加；DAP12能够显著抑制糖酵解途径；DAP12在肝癌细胞胞质和线粒体中均有表达；细胞中DAP12能够抑制糖酵解及线粒体氧化呼吸功能；DAP12与PKM2之间存在相互作用，DAP12能够抑制PKM2在蛋白水平的表达。证实DAP12是一个与肝细胞肝癌发生发展相关的重要抑癌基因。DAP12能够通过抑制糖酵解途径，抑制肝癌发生、发展。本研究有助加深对DAP12在肝癌发生发展中作用的理解，并有可能发现潜在的治疗靶点和预后指标。