接头蛋白DAP12抑制肝癌发生发展的作用及机制研究

DAP12, an adaptor protein of ITAM-dependent receptors, could transduce the inflammatory signals mediated by the receptors. In recent years, ITAM-dependent receptors in carcinogenesis and development of hepatocelullar carcinoma (HCC) was gradually awared by researchers. However, the role of DAP12 in carcinogenesis and development of HCC remains unknown. The results of our preliminary experiments showed that DAP12 expression was reduced in HCC cells, and DAP12 suppressed cell growth and metastasis. There was an interaction between DAP12 and MyD88. DAP12 expression was reduced in the tumor tissue of HCC and was correlated with poor prognosis. In additon, DAP12 overexpression could significantly suppress MyD88 and its downstream signaling of NF-κB and MAPK. Based on the results, we hypothesized that DAP12 could suppress HCC carcinogenesis and development by downregulating MyD88. This study will clarify the role of DAP12 in HCC by in vitro and in vivo assays. Moreover, we aim at revealing the mechanisms by detection of influence of DAP12 on MyD88 in HCC. Moreover, the clinical prognostic value of DAP12 will be testified. The study helps to deepen the understanding of DAP12 in the occurrence and development of HCC, and may offer a potential therapy target and prognostic marker.

DAP12是ITAM依赖性受体共同的接头蛋白，负责调控该类受体介导的炎性信号。近年来，ITAM依赖性受体在肝癌发生中的作用逐渐得到重视，但DAP12对于肝癌发生的作用尚未明晰。本课题组前期研究发现：DAP12在肝癌组织及细胞中表达减低、DAP12缺失与肝癌患者预后不良有关；DAP12过表达抑制肝癌细胞生长和转移肿瘤生物学行为；DAP12与MyD88直接相互作用并抑制其下游NF-κB和MAPK信号通路。在上述工作基础上，我们提出：DAP12能够通过下调MyD88通路介导的炎症信号，抑制肝癌发生、发展的假设。拟用体内外实验研究DAP12在肝癌发生发展中的作用；深入分析DAP12通过MyD88影响肝癌发生发展的生物学效应及分子机制；并初步探索DAP12在肝癌临床预后上的价值。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。

DAP12是ITAM依赖性受体共同的接头蛋白，负责调控该类受体介导的炎性信号。近年来，ITAM依赖性受体在肝癌发生中的作用逐渐得到重视，但DAP12对于肝癌发生的作用尚未明晰。本课题组研究发现：DAP12在肝癌组织及细胞中表达减低；DAP12表达下调与肿瘤恶性临床病理特征及不良预后显著相关；DAP12过表达能够在体外及体内抑制肝癌细胞生长和转移肿瘤生物学行为；DAP12过表达显著抑制肝癌细胞糖酵解途径及线粒体呼吸功能从而抑制Warburg效应。证实了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。