黄嘌呤氧化还原酶（XOR）调控非酒精性脂肪性肝炎来源HCC炎癌转化进程的机制研究

非酒精性脂肪性肝炎（NASH）已逐渐成为诱发我国肝细胞性肝癌（HCC）的重要因素，该病理进程相关的炎症微环境、异常代谢、DNA损伤等机制目前仍知之甚少。本研究旨在阐明黄嘌呤氧化还原酶（XOR）在NASH来源HCC炎癌转化进程中的表达、作用及其潜在机制。前期基于临床样本及条件性基因敲除小鼠NASH来源HCC模型已初步发现XOR在该病理进程中存在差异性表达且具有重要作用。本课题拟进一步基于大量临床样本，通过小鼠体内NASH来源HCC模型，肝癌前体细胞种植模型，转录组学、蛋白及代谢质谱学分析，免疫共沉淀及免疫荧光分析，体外肝癌细胞及原代肝细胞功能学分析，分子抑制剂等手段进行进一步研究，旨在明确XOR调控NASH来源HCC炎癌转化进程中炎症微环境、DNA损伤以及代谢改变情况及其潜在机制，探究其作为监测肝癌患者预后以及靶向治疗肝癌的价值。以期为肝癌的诊断与治疗提供潜在的生物靶标。

Nonalcoholic steatohepatitis (NASH) is one of the major drivers for the rising trend in hepatocellular carcinoma (HCC) in China. Little is known about the inflammatory micro-environment, abnormal metabolism, and DNA damage associated with this pathological process. The purpose of this study is to elucidate the expression, role and underlying mechanism of xanthine oxidoreductase (XOR) in the inflammation-cancer transformation of HCC in the source of NASH. Our previous work has revealed the abnormal expression pattern and important role of XOR in this pathological process based on large amounts of clinical samples and NASH associated HCC models in conditional knockout mice. This project aims to interpret the function of XOR on inflammatory micro-environment, DNA damage, and metabolic changes and their potential mechanisms during the conversion process of HCC from NASH source with a serial of experiments including mice NASH associated HCC models, mice HCC model of liver cancer precursor cells, transcriptome, protein and metabolic mass spectrometry, immunoprecipitation and immunofluorescence analysis, in vitro hepatoma cells and primary hepatocyte function analysis, molecular inhibitors and other means. In addition, to explore the value of XOR as monitoring prognosis and targeted treatment of HCC. In order to provide a potential biological target for the diagnosis and treatment of liver cancer.