Gankyrin介导的巨噬细胞自噬负调控IL-1beta生成抑制肝炎恶性转化的机制研究

自噬作为一种细胞自稳机制，参与细胞稳态维持和免疫应答，其活性改变与肿瘤发生发展密切相关。但是，巨噬细胞自噬在肝癌发生中的作用和机制尚不清楚。申请者前期发现Gankyrin是炎-癌转化中的关键节点分子，其成果受到国内外同行关注。我们最新发现，它在炎癌转化中发挥了双重作用：肝细胞缺失Gankyrin小鼠肝癌发生减少，全身缺失和巨噬细胞中缺失却导致肝癌增多，提示肝细胞中它作为癌基因，巨噬细胞中却作为了抑癌基因。而且，巨噬细胞中Gankyrin缺失导致自噬减弱，IL-1beta生成增多，提示Gankyrin可能通过巨噬细胞自噬限制炎症抑制肝癌发生，相关研究尚未见报道。这也强烈提示巨噬细胞自噬可能是影响肝癌发生的重要因素。本项目将以肿瘤微环境中Gankyrin对巨噬细胞功能和自噬水平调控为切入点，探讨Gankyrin介导的巨噬细胞自噬对肝炎恶性转化的调控作用，以期为肿瘤防治提供新的药物靶点。

Autophagy is a ubiquitous cellular process that regulates cell growth, survival, development and death. Autophagy is closely intertwined with inflammatory and immune responses. In the liver, hepatocyte basal autophagy is critical to maintain liver homeostasis and loss of basal hepatocyte autophagy leads to liver injury, inflammation, fibrosis and tumorigenesis. Hepatic inflammation is a pathogenic process associated with various types of acute and chronic liver disorders, and it contributes to progressive liver injury and fibrosis. Hepatic macrophages are the major (80–90%) resident macrophages of the body and are central in regulating the pathogenesis of acute and chronic liver injury. While macrophage-mediated inflammatory responses can be hepatoprotective by promoting resolution and repair of tissue injury, excessive macrophage activation is detrimental by exacerbating liver injury of various conditions. However, the role of macrophage autophagy in the liver pathogenesis is less known. In the previous three years, we have elucidated the important role of Gankyrin in hepatocytes by regulating cancer stem cell and autophagy to promote the malignant transformation. Recently, we surprisingly found that oncoprotein Gankyrin plays the contradictory role in hepatocytes and macrophages during hepatocarcinogenesis. Deletion of Gankyrin in hepatocytes decreased DEN-induced HCC, whereas deletion in whole body or in macrophages significantly increased HCC. Moreover, deficiency of Gankyrin in macrophage diminished autophagy but enhanced IL-1beta production. Taken together, we proposed that Gankyrin regulate macrophage autophagy to limit inflammation and HCC. In this project, we will further explore the role of Gankyrin in macrophage, and predict the candidate molecules in controlling macrophage autophagy in HCC. Collectively, our study will provide a novel and critical regulator of autophagy and inflammation, and provide a new treatment strategy for HCC.