维生素D水平与慢性肝炎-肝癌预后的孟德尔随机化研究

慢性肝炎是肝细胞肝癌（Hepatocellular Carcinoma, HCC）发生的最主要原因。高复发率和高转移率严重制约着HCC生存率的提高。功能性研究表明维生素D在肿瘤免疫、细胞凋亡、入侵转移过程中均发挥重要作用。流行病学证据和本课题组前期研究也发现25(OH)D水平与HCC患者的生存时间显著相关，但二者的因果关联尚不明确。本研究拟结合两样本孟德尔随机化研究和队列研究的方法，分析影响维生素D水平的遗传变异与维生素D水平及HCC生存和复发的关联度，明确维生素D水平与慢性肝炎-肝癌预后的因果关联。采用双荧光素酶报告基因系统、Co-IP、CHIP、PDX肝癌模型等技术，阐明维生素D对肝癌细胞增殖、凋亡、侵袭迁移能力及SOCS2表达水平的影响；探索维生素D调控SCOS2/JAK/STAT通路抑制HCC进展的生物学机制，为改善HCC个性化治疗，提高患者生存率提供新思路和理论依据。

Chronic hepatitis is the predominant cause of hepatocellular carcinoma (HCC). Although there are modern treatment methods, such as targeted therapy and immunotherapy, to improve the prognosis of patients with HCC, the high recurrence and metastasis rate of HCC severely restricts the improvement of mortality. Functional experiments have found that vitamin D plays an important role in tumor immunity, cell apoptosis, invasion and metastasis of cancer cells. Epidemiological evidence and our previous finding showed that there was a significant association between plasma 25(OH)D level and the overall survival time in patients with HCC. But the causal relationship between vitamin D and HCC prognosis remains unclear. This study will combine two-sample Mendelian Randomization (MR) approach with prospective cohort study to test the association between SNPs which affect vitamin D level and vitamin D concentration, as well as the association of those SNPs with HCC overall survival and disease-free survival. We aim to clarify the real causal link between vitamin D and the prognosis of HCC induced by chronic hepatitis. In addition, a series of molecular biology technologies, like dual luciferase reporter gene system, Co-IP, ChIP, PDX model were adopted in this study. Based on these technologies, we aim to clarify the effects of vitamin D on the proliferation, apoptosis, invasion and migration, and the expression level of SOCS2, and to explore the biological mechanism vitamin D inhibits HCC progression via regulating SOCS2/JAK/STAT pathway. To sum up, we aim to provide innovative strategy and theoretical basis for improving the personalized treatment and survival rate for patients with HCC induced by chronic hepatitis.