内质网应激蛋白NOGO家族B亚型调控脂质自噬在NAFLD相关肝癌中的分子机制研究

The growing epidemic of obesity, which causes increasing number of Non-alcoholic fatty liver disease (NAFLD) and NAFLD-associated hepatocellular carcinoma (HCC), has paralleled the increasing incidence of HCC. Although ER stress and lipid metabolism disorder are two defining features closely linked to NAFLD-HCC, the molecular mechanisms remained unclear. Using various databases, we selected a novel oncogene in NAFLD-HCC, NOGO-B, which plays a key role in ER stress. Our previous data demonstrated that NOGO-B promoted HCC cell growth, lead to cell autophagy, and enhanced lipid metabolized ability. Based on these results, we aim to further investigate the potential function. We will establish a high fat high carbohydrate induced NAFLD-HCC model, combined with Lentivirus induction, to explore essential roles of NOGO-B in lipid metabolism, hepatic tumorigenicity, and cell autophagy. Our study will uncover novel metabolic mechanisms of NAFLD-HCC, providing a new candidate biomarker and strategy to the treatment of HCC in obese people.

近年来随着肥胖的流行，由其引起的非酒精性脂肪性肝病（NAFLD）明显增多，相关肝癌的发生率也显著上升。内质网应激和脂质代谢紊乱与NAFLD相关肝癌的发生发展有密切联系，但其分子机制尚不明确。我们利用既有数据库筛选出在肝癌中差异表达的内质网应激相关基因，即NOGO-B。前期结果表明，NOGO-B可以促进肝癌细胞的增殖，提高细胞自噬水平，促进脂质利用。本项目在此基础上，将构建NAFLD相关肝癌的小鼠模型，采用高脂高糖饲养、慢病毒感染等方法，从代谢调节、肝癌形成、脂质自噬等方面研究NOGO-B在NAFLD及其相关肝癌中的分子机制，以期进一步揭示NAFLD相关肝癌的发病机制，为临床肥胖肝癌病人的治疗提供新的分子标志和治疗靶点。

非酒精性脂肪性肝病是代谢综合征的肝内表现，可以明显促进肝癌的发生。近期报道显示，脂质代谢紊乱是癌症发展过程中的重要特征之一，但是，在非酒精性脂肪肝相关肝癌中的脂质代谢调控机制尚不清楚。我们发现ER定位蛋白Nogo-B的表达在非酒精性脂肪肝相关肝癌病人中明显上调。并且，在小鼠模型中，Nogo-B也可以有效地促进高脂高糖引起的非酒精性脂肪肝相关肝癌及脂肪肝进程。机制方面，CD36介导的oxLDL摄入可以通过转录因子CEBPβ激活Nogo-B的表达。高表达的Nogo-B与自噬相关基因ATG5相互作用，促进脂滴自噬过程，从而提高LPA的含量。升高的LPA使YAP发生去磷酸化，激活YAP活性，增加CYR61和CTGF等下游基因的表达，最终促进肝癌细胞增殖。通过本项目的研究，CD36-Nogo-B-YAP信号通路通过促进oxLDL的代谢重编程，诱发非酒精性脂肪肝相关肝癌。这一发现为临床代谢紊乱相关癌症的治疗提供了新的潜在靶点和治疗策略。