高胆固醇血症对肝癌发生发展的影响和机制研究

The incidence of metabolic diseases is increasing year by year, which has become a major medical problem in the world. High cholesterol (or hypercholesterolemia) is closely associated with many diseases, such as atherosclerosis, coronary heart disease and stroke. Now, increasing concentration have been applied on the relationship between high cholesterol and cancer. Some epidemiological studies demonstrated that there was a negative correlation between the level of total serum cholesterol and the incidence of liver cancer. But other studies also revealed that peoples using statins, a kind of colesterol-lowering drug, had a reduced risk of liver cancer. So the influence of abnormal cholesterol metabolism on the incidence of liver cancer is still controversial, and experimental studies are needed to clarify this important issue. In this project, we will combine evidence-based medicine and basic medical research. Firstly, the clinical data will be collected to analyze the effect of high cholesterol on the occurrence and progression of liver cancer. Then diet-induced and genotype-induced hypercholesterolemia models will be established to study the mechanism and key signaling pathways of high cholesterol on regulating the development and progression of liver cancer, which may provide new strategies for prevention and treatment of liver cancer.

代谢性疾病的发病率逐年升高，其预防和治疗已成为重大的医学难题。高胆固醇血症与动脉粥样硬化、冠心病、脑卒中等疾病密切相关，其与肿瘤发生发展的关系也逐步受到重视。部分流行病学调查表明血液中总胆固醇水平与肝癌发病率呈负相关，但还有部分调查显示使用降胆固醇药物（他汀类药物）人群的肝癌发病率亦降低，可见胆固醇代谢异常对肝癌发生的影响尚有争议，目前还缺乏实验研究明确这一问题。本项目将结合循证医学和基础医学研究方法，一方面广泛检索、收集并分析临床数据，明确高胆固醇血症对肝癌发生及恶性进展的影响；另一方面构建饮食诱导型和基因诱导型高胆固醇血症动物模型，研究血胆固醇升高对肝癌发生、原位生长和远处转移的影响，并结合体内外实验结果，阐明作用机制，明确关键信号通路和分子事件，为肝癌防治提供新思路和新策略。

高胆固醇血症与动脉粥样硬化、冠心病、脑卒中等疾病密切相关，其与肿瘤发生发展的关系也逐步受到重视。部分流行病学调查表明血液中总胆固醇水平与肝癌发病率呈负相关，但还有部分调查显示使用降胆固醇药物（他汀类药物）人群的肝癌发病率亦降低，可见胆固醇代谢异常对肝癌发生的影响尚有争议，目前还缺乏实验研究明确这一问题。本项目结合循证医学和基础医学研究方法，一方面广泛检索、收集并分析临床数据，明确高胆固醇血症对肝癌发生及恶性进展的影响；另一方面构建饮食诱导型和基因诱导型高胆固醇血症动物模型，研究血胆固醇升高对肝癌发生、原位生长和远处转移的影响，并结合体内外实验结果，阐明作用机制，明确关键信号通路和分子事件。. 本课题通过大规模的人群队列研究，发现血胆固醇水平与人群肝癌发生率呈负相关。通过对肝癌患者的术后随访，发现肝癌患者术前血胆固醇水平与其术后复发、转移和生存亦呈负相关。同时，利用不同的高胆固醇血症动物模型，联合多种诱癌手段和复发转移模型，明确体内高胆固醇水平可增加自然杀伤细胞（NK）的胆固醇含量和脂筏形成，促进NK细胞激活性受体（NCR1和NKG2D等）在脂筏中的定位，激活其下游信号通路，进而增强NK细胞的抗肿瘤能力，抑制肝癌发生和恶性进展。通过调控LDLR/PCSK9代谢通路，可明显增加NK细胞的胆固醇水平，增强其抗肿瘤效应，为肝癌免疫治疗提供了新策略。.