中性粒细胞外诱捕网诱发线粒体功能障碍在缺血再灌注损伤促进肝癌复发转移过程中的作用机制研究

缺血再灌注损伤（IRI）是肝癌（HCC）复发转移的重要因素。本团队前期研究发现IRI能诱发中性粒细胞外诱捕网（NETs）形成，并通过释放IL-17A促进HCC复发转移，但机制不明。研究发现NETs能诱发线粒体功能障碍，且伴PGC1A通路激活和SUCLG2表达异常。由此，我们提出假设IRI通过NETs释放IL-17A诱发线粒体功能障碍促进HCC复发转移，PGC1A/SUCLG2通路在此过程中发挥重要作用。本实验拟在前期研究基础上，通过应用PAD4敲除鼠、人和鼠源肝癌细胞系及IL-17A特异性抗体，从细胞、动物和临床水平进一步确定NETs释放IL-17A诱发线粒体功能障碍在IRI促进HCC复发转移过程中的作用；明确IL-17A调控PGC1A/SUCLG2通路机制；探究SUCLG2缺失对肝细胞恶性转化的影响。并通过本研究为HCC防治提供新策略。

Ischemia and reperfusion injury (IRI) is one of the major risk factors for the recurrence and metastasis of hepatocellular carcinoma (HCC). Previous studies have shown that IRI promotes HCC development by inducing neutrophil extracellular traps (NETs) formation and releasing large amounts of IL-17A, but the mechanism is still unclear. Further studies revealed that NETs could induce mitochondrial dysfunction, accompanied by activation of PGC1A signaling pathway and deletion of SUCLG2. Thus, we hypothesize that IRI promotes recurrence and metastasis of HCC, via inducing mitochondrial dysfunction by NETs, and the PGC1A/SUCLG2 signaling pathway plays an important role in this process. Based on the previous studies, we will further determine the role of NETs inducing mitochondrial dysfunction in the process of IRI promoting recurrence and metastasis of HCC, from the perspective of cell, animal and clinic. We will use PAD4KO mouse and human and murine liver cancer cell lines. Then we will clarify the mechanism by which IL-17A regulates PGC1A/SUCLG2 signaling pathway, and explore the ability of SUCLG2 deletion to transform hepatocytes into tumor cells. Through this study, we will provide new strategies for the prevention and treatment of HCC.