STAT4基因多态与HBV相关肝癌发病风险关联的分子机制研究

肝癌是我国第三大恶性肿瘤，HBV是其主要的危险因素。我们最近开展的一项GWAS，发现JAK-STAT信号通路的重要成员--STAT4基因的多态位点与HBV相关肝癌的发病风险显著关联（Nature Genetics 2013, 45:72-5）。本项目拟探讨该关联存在的分子机制：1）通过GWAS数据的深入分析以及六组大规模样本的验证实验，对与肝癌发病风险关联的STAT4基因区域进行精细定位，确定潜在的功能性多态位点；2）通过UCSC和ENCODE等数据库的搜索与分析，对这些多态位点进行功能注释；3）通过一系列分子、细胞和动物实验，鉴定真正的功能性多态位点，并揭示其作用机制；4）在500例以上肝癌手术病人中，分析STAT4基因多态位点、STAT4及其下游靶基因的表达水平与肝癌各种临床表型及预后之间的关系。本研究将有助于深入理解STAT4在肝癌发生发展中的作用，为应用其预防和治疗肝癌打下基础。

Hepatocellular carcinoma (HCC) is the third most common and deadly cancer in China. Hepatitis B virus (HBV) is the most important risk factor of HCC. Recently, we performed a genome-wide association study (GWAS) and found the association between the risk of HBV-related HCC and genetic variants of STAT4, which is the core member of JAK-STAT signaling pathway (Nature Genetics 2013, 45:72-5). This project is proposed to investigate the mechanism of this association: 1) Perform fine mapping of the region among STAT4 that is associated with the risk of HBV-related HCC through deep analysis of the GWAS data followed by confirmation in six huge independent samples to identify the potential functional SNPs in STAT4. 2) Perform functional annotation of the potential functional SNPs through searching and analyzing the online database, such as UCSC and ENCODE, and so on. 3) Perform a series of molecular, cell and animal experiments to identify the real functional SNP and reveal its potential molecular mechanism. 4) Perform clinical data analysis of more than 500 HCC samples to investigate the relationship between clinical phenotypes and the genetic variants in STAT4 as well as gene expression of STAT4 and it's downstream genes. If successfully implemented, this study has the potential to significantly improve the understanding of the role of STAT4 in the development of HCC, which will contribute to its application on prevention and treatment HCC.