Hepatocellular carcinoma risk variant modulates lncRNA HLA-DQB1-AS1 expression via a long-range enhancer–promoter interaction

生物 增强子 单核苷酸多态性 全基因组关联研究 肝细胞癌 等位基因 表达数量性状基因座 遗传学 SNP公司 癌基因 癌症研究 转录因子 基因型 基因 细胞周期
作者
Haoxue Wang,Beifang Yang,Xiaomin Cai,Xiang Cheng,Na Shen,Li Liu,Jiaoyuan Li,Ying Wang,Heng He,Pingting Ying,Bin Li,Zequn Lu,Nan Yang,Xiaoyang Wang,Fuwei Zhang,Yanmin Li,Wenzhuo Wang,Caibo Ning,Ying Zhu,Jiang Chang,Xiaoping Miao,Jianbo Tian,Rong Zhong
出处
期刊:Carcinogenesis [Oxford University Press]
卷期号:42 (11): 1347-1356 被引量:10
标识
DOI:10.1093/carcin/bgab095
摘要

Abstract Substantial evidence highlighted the critical role of long non-coding RNAs (lncRNA) in driving hepatocarcinogenesis. We hypothesized that functional variants in genome-wide association studies (GWASs) associated loci might alter the expression levels of lncRNAs and contribute to the development of hepatocellular carcinoma (HCC). Here, we prioritized potentially cis-expression quantitative trait loci-based single nucleotide polymorphism (SNP)-lncRNA association together with the physical interaction by the analyses from Hi-C data in GWAS loci of chronic hepatitis B and HCC. Subsequently, by leveraging two-stage case-control study (1738 hepatitis B [HBV]) related HCC cases and 1988 HBV persistent carriers) and biological assays, we identified that rs2647046 was significantly associated with HCC risk (odds ratio = 1.26, 95% CI = 1.11 to 1.43, P = 4.14 × 10−4). Luciferase reporter assays and electrophoretic mobility shift assays showed that rs2647046 A allele significantly increased transcriptional activity via influencing transcript factor binding affinity. Allele-specific chromosome conformation capture assays revealed that enhancer with rs2647046 interacted with the HLA-DQB1-AS1 promoter to allele-specifically influence its expression by CTCF-mediated long-range loop. Cell proliferation assays indicated that HLA-DQB1-AS1 is a potential oncogene in HCC. Our study showed HLA-DQB1-AS1 regulated by a causal SNP in a long-range interaction manner conferred the susceptibility to HCC, suggesting an important mechanism of modulating lncRNA expression for risk-associated SNPs in the etiology of HCC.
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