DDX5/p62相互作用调控细胞自噬-炎症抑制非酒精性脂肪性肝炎相关肝癌进展的作用及机制研究

Non-alcoholic steatohepatitis-associated hepatocellular carcinoma (NASH-HCC) is a malignancy whose incidents is rapidly increasing. To date, no evidence-based drug therapy has been approved for NASH management. To identify new target and develop target-based drug are important strategies for preventing NASH to HCC progression. P62 is the key signaling in promoting NASH-HCC progression. Previously, we found DDX5 decreased in mouse models of NASH and NASH-HCC. DDX5 expression inversely correlates with p62, but positively with the good prognosis in NASH-HCC patients. DDX5 interacted with p62 to promote autophagy and p62 degradation. Hypercalin B could increase the DDX5 protein level but not the mRNA level, indicating its potential role in NASH-HCC therapy. Based on these data, this project intends to study the mechanisms of DDX5 and p62 interaction by regulating autophagy and inflammation suppressing NASH-HCC progression; the mechanism of Hypercalin B increasing DDX5 protein level; employing the DDX5 conditional knockin/knockout mice to establish NASH-HCC mouse models, investigating the effect and mechanism of Hypercalin B. Finally, uncover the mechanisms of DDX5 in NASH-HCC progression, shed light on the mechanism of Hypercalin B regulating DDX5 protein in suppressing NASH associated HCC.

非酒精性脂肪性肝炎（NASH）所致肝癌的发病率呈上升趋势，临床上尚无有效控制NASH及进展的药物，发现和确证NASH相关肝癌进展中新靶点并研发药物是预防和治疗NASH相关肝癌的重要手段。p62是促进NASH相关肝癌的关键蛋白。前期研究发现DDX5在NASH相关肝癌小鼠模型中下调，DDX5表达量与p62负相关，与肝癌病人预后正相关。DDX5与p62互作促进自噬及p62降解。Hypercalin B（HB）可上调DDX5蛋白，提示其在NASH相关肝癌治疗上有一定的潜力。据此本项目拟在体内外模型中研究DDX5与p62互作调控自噬及炎症抑制NASH相关肝癌进展的分子机理；研究HB上调DDX5蛋白的分子机制，利用DDX5肝脏条件性高表达或敲除小鼠探索其在NASH相关肝癌模型中药效与作用机制；最终阐明DDX5抑制NASH相关肝癌进展的机理，揭示HB调控DDX5在体内外抗NASH相关肝癌的分子机制。

非酒精性脂肪性肝炎（NASH）所致肝癌的发病率呈上升趋势，临床上尚无有效控制NASH及进展的药物，发现和确证NASH相关肝癌进展中新靶点并研发药物是预防和治疗NASH相关肝癌的重要手段。本项目系统阐明了DDX5调控mTOR信号通路抑制NASH及相关肝癌进展的分子机制，为NASH相关肝癌的治疗提供了潜在新靶点。本项目发现：1）在NASH及相关肝癌病人、模型小鼠肝脏组织中DDX5表达量显著下降，且与预后差密切相关；2）高表达或敲降DDX5分别缓解或加剧NASH病理水平、抑制或促进肝癌发生；3）DDX5抑制mTORC1信号通路改善脂代谢、促进自噬水平、抑制NLRP3炎症小体激活缓解NASH进展；4）在肝癌细胞中，DDX5阻断p62/TRAF6相互作用抑制mTOR的K63位泛素化激活，从而促进自噬，抑制肝癌发生发展；5）在脂质异常沉积的正常肝实质细胞中，DDX5通过招募TSC1/2复合物至mTOR抑制mTORC1激活；6）天然活性分子Hyperforcinol K与DDX5直接结合阻断E3连接酶TRIM5介导的DDX5泛素化降解，从而缓解NASH进展。本项目详细阐述了DDX5在正常肝实质细胞、肝癌细胞调控mTOR信号通路改善脂代谢、促进自噬、抑制炎症小体激活，抑制NASH及肝癌演进的新分子机制。发现了间苯三酚类化合物Hyperforcinol K直接靶向DDX5发挥抗NASH-HCC作用的全新药理机制，可为抗NASH及相关肝癌的药物研发提供潜在新靶点和先导化合物，为临床抗NASH-HCC治疗提供新思路，最终为开发我国具有自主知识产权的新药奠定基础。

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