Shen Na, Gong Jing, Wang Ying, Tian Jing, Qian Jiaming, Zou Li, Chen Wei, Zhu Beibei, Lu Xinghua, Zhong Rong, Guo Anyuan, Wang Li, Miao Xiaoping
State Key Laboratory of Environment Health (Incubation), MOE (Ministry of Education) Key Laboratory of Environment & Health, Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), and Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences; School of Basic Medicine, Peking Union Medical College, Beijing, China.
State Key Laboratory of Environment Health (Incubation), MOE (Ministry of Education) Key Laboratory of Environment & Health, Ministry of Environmental Protection Key Laboratory of Environment and Health (Wuhan), and Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
PLoS One. 2014 Sep 8;9(9):e107246. doi: 10.1371/journal.pone.0107246. eCollection 2014.
The human forkhead box A1 (FOXA1) and A2 (FOXA2) transcription factors have been found to control estrogen and androgen signaling through co-regulating target genes with sex hormone receptors. Here we used an integrative strategy to examine the hypothesis that genetic variants at FOXA1/2 binding elements may be associated with sexual dimorphism of hepatocellular carcinoma (HCC) risk. Firstly we extracted chromatin immunoprecipitation-sequencing (ChIP-seq) data of FOXA1, FOXA2 and estrogen receptor 1(ERα) from ENCODE database to obtain dual target regions of FOXA/ERα, and further intersected these regions with genes' promoters. Then we used MATCH program to predict FOXA binding elements, in which genetic variants were retrieved by dbSNP database (NCBI, build 134). A total of 15 candidate variants were identified in this stage. Secondly we performed a case-control study with 1,081 HCC patients and 2,008 matched controls and found a significant association of SERPINA6-rs1998056 with female HCC risk under common genetic models (e.g. GG versus CC: OR = 2.03, 95% CI = 1.26-3.27, P = 0.004). Moreover, results from our real-time quantitative polymerase chain reaction (qPCR) using 72 normal liver tissues adjacent to the tumors showed that SERPINA6 expression was significantly different among different genotypes of this variant (GG versus CC: P = 0.032; Group test: P = 0.060). In summary, our study suggested that SERPINA6-rs1998056 regulated by FOXA/ERα might be associated with female HCC risk.
人类叉头框A1（FOXA1）和A2（FOXA2）转录因子已被发现可通过与性激素受体共同调节靶基因来控制雌激素和雄激素信号传导。在此，我们采用综合策略来检验以下假设：FOXA1/2结合元件处的基因变异可能与肝细胞癌（HCC）风险的性别差异有关。首先，我们从ENCODE数据库中提取了FOXA1、FOXA2和雌激素受体1（ERα）的染色质免疫沉淀测序（ChIP-seq）数据，以获得FOXA/ERα的双重靶区域，并进一步将这些区域与基因启动子进行交叉分析。然后，我们使用MATCH程序预测FOXA结合元件，其中的基因变异通过dbSNP数据库（NCBI，版本134）检索。在此阶段共鉴定出15个候选变异。其次，我们对1081例HCC患者和2008例匹配对照进行了病例对照研究，发现在常见遗传模型下，SERPINA6-rs1998056与女性HCC风险存在显著关联（例如，GG与CC比较：OR = 2.03，95%CI = 1.26 - 3.27，P = 0.004）。此外，我们使用72例肿瘤旁正常肝组织进行的实时定量聚合酶链反应（qPCR）结果显示，该变异的不同基因型之间SERPINA6表达存在显著差异（GG与CC比较：P = 0.032；组间检验：P = 0.060）。总之，我们的研究表明，受FOXA/ERα调控的SERPINA6-rs1998056可能与女性HCC风险相关。
