NOD2通过AMPK通路对肝细胞肝癌的抑癌效应及分子机制

Hepatocellular carcinoma(HCC) is one the most common malignancy with high attack rate and mortality in China. Exploring it molecular mechanism and discovering novel molecular therapy target are effective strategies to improve the survival rate and survival quality of HCC patients. Extensive investigation of the molecular mechanism involved in the progression of HCC and identification of effective target of molecular therapy may provide effective therapeutic strategy to control and reverse HCC.NOD2 is an important molecule in the innate immune system. Recent years, it proved that some innate immune molecules play important role in carcinogenesis and tumor development. Our previous study indicated that NOD2 expression was significantly downregulated in HCC cells compared with that in the corresponding non-cancerous liver tissues. Further in vitro and in vivo biological function analysis showed that exogenous overexpression of NOD2 in HCC cells significantly decreased the malignant behaviors of HCC cells, and the anti-tumor effect of NOD2 was dependent on activation of AMPK pathway in HCC cells.In this study, we are going to increase the size of clinical samples and further validate the deregulation of NOD with clinical parameters of HCC patients. We are going to further investigate the molecular mechanisms involved in its deregulation. After efficiently validate the anti-tumor effect of NOD2 on hepatocarcinoma cells, we will further investigate the effect of NOD2-AMPK signaling transduction pathway in HCC cells and identify the key molecular mechanism involved in it.The related results will further be validated in cellular model, animal model and clinical specimen. Thus we are going to clarify the molecular mechanism involved in the anti-tumor effect of NOD2 on HCC cells, and further investigate the possibility of exploring it as a molecular target therapy strategy for hepatocellular carcinoma.

肝细胞肝癌是我国临床发病率和致死率都较高的恶性肿瘤，而从分子水平深入探索其进展机制是有效控制和逆转肝癌的重要手段。申请者基于多年在肿瘤免疫的研究基础，率先探索了免疫分子NOD2在肝细胞肝癌中的表达状况与作用效应。结果显示，与相对应非癌肝组织相比，NOD2在肝癌组织细胞中的表达显著下调和缺失，而NOD2在肝癌细胞中的外源性过表达能够通过活化AMPK通路发挥显著的抑癌效应，提示免疫分子NOD2有抑癌基因的新功能，而NOD2的表达失调参与了肝癌进程。本项目拟在前期研究结果的基础上，在细胞模型、动物模型和扩大的临床标本中探索NOD2在肝癌中表达失调的分子机制，以及NOD2活化AMPK轴并进一步对肝癌细胞发挥抑癌效应的分子机制，以求阐明NOD2表达失调参与肝癌进程的机制和关键结构域，探索将其开发为肝癌早期诊断的分子标记物及肝癌靶向治疗新型靶标的可能性。

肝细胞肝癌（Hepatocellular carcinoma, HCC）的高发病率和高死亡率严重威胁着人类健康。大多数肝癌患者一经诊断即为晚期肝癌，失去了手术切除的机会。而从分子水平深入探索其进展机制是有效控制和逆转肝癌的重要手段。NOD2和NOD1是细胞内NOD样受体家族的经典成员，属于固有免疫危险信号的感受器分子。近期研究表明，许多固有免疫受体也参与了肿瘤进展的调控，这提示NOD2及其同家族成员NOD1可能在肿瘤进展中也发挥一定的调控作用。本项目率先探索了固有免疫分子NOD2及其同家族成员NOD1在肝癌中的表达、作用效应和分子机制。结果显示，NOD2和NOD1蛋白在肝癌临床标本中的表达量显著下调或缺失，且其在肝癌中的表达水平与肝癌患者的临床分期、病理分级等指标负相关，提示NOD2及NOD1蛋白的表达下调或缺失参与了HCC的疾病进展。进一步研究显示，NOD2和NOD1蛋白在肝癌的进展中发挥显著的抑癌效应。NOD2通过直接结合LKB1-AMPKα复合物激活HCC细胞中的AMPK信号通路发挥其抑制HCC疾病进展及增强HCC细胞化疗敏感性的作用。而NOD1通过直接结合SRC抑制HCC细胞中SRC-MAPK信号轴发挥其抑制HCC疾病进展及增强HCC细胞的化疗敏感性的作用。该研究为阐明肝癌的进展机制及新型治疗策略的研发奠定了基础。该项目的研究成果发表了标注项目资助号的SCI收录论文7篇，相关成果发表在Cell death and differentiation, oncogene 和Cell death and diseases等国际权威期刊上。该项目申报国家发明专利三项，其中两项获得了国家发明专利的授权。该项目的研究成果在第17届国际免疫学大会报告，并多次在国内学术会议上进行交流报告，引起了国内外同行的热烈讨论和好评。