Wu Shenshen, Wang Shizhi, Fu You, Tang Weiyan, Jin Hua, Meng Qingtao, Zhang Chengcheng, Cui Mengjing, Cao Xiaoli, Li Xiaobo, Zhang Zhengdong, Chen Rui
State Key Laboratory of Bioelectronics, Southeast University, Nanjing, China.
Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China.
Int J Cancer. 2017 Feb 15;140(4):756-763. doi: 10.1002/ijc.30490. Epub 2016 Nov 18.
Recently, several studies have showed that FAS (rs2234767, rs1800682) and FASL (rs763110) functional single nucleotide polymorphisms (SNPs) were associated with the risk of various cancers. However, the association between cervical cancer risk and the three SNPs above remained inconclusive. In this work, we performed a two-stage case-control study on 1155 cervical cancer patients and 1252 matched healthy controls to determine the roles of the mentioned SNPs in cervical cancer susceptibility. We genotyped the FAS rs2234767, rs1800682, and FASL rs763110 polymorphisms using PCR-TaqMan assays. Results revealed that the rs763110 TT genotype significantly increased the risk of cervical cancer compared with the CC/CT genotype (adjusted OR = 1.70, 95% CI = 1.19-2.42). However, we did not observe any association between the cervical cancer risk and the rs2234767 and rs1800682 polymorphisms. The immunohistochemistry assay showed that patients carrying the rs763110 TT genotype presented a lower cancerous FASL expression than that of the CC/CT genotypes. Chromatin immunoprecipitation (ChIP) and Sequential Chromatin immunoprecipitation assays also demonstrated that OCT1 was recruited to the FASL promoter region and regulated the FASL gene transcription by interacting with C/EBPβ. In conclusion, this study provided evidence indicating that the rs763110 variant in the FASL promoter was associated with the risk of cervical cancer by affecting the binding affinity of the C/EBPβ/OCT1 complex to chromatin.
最近，多项研究表明，FAS（rs2234767、rs1800682）和FASL（rs763110）功能性单核苷酸多态性（SNP）与多种癌症风险相关。然而，上述三种SNP与宫颈癌风险之间的关联仍无定论。在本研究中，我们对1155例宫颈癌患者和1252例匹配的健康对照进行了两阶段病例对照研究，以确定上述SNP在宫颈癌易感性中的作用。我们使用PCR-TaqMan分析法对FAS rs2234767、rs1800682和FASL rs763110多态性进行基因分型。结果显示，与CC/CT基因型相比，rs763110 TT基因型显著增加了宫颈癌风险（校正OR = 1.70，95% CI = 1.19 - 2.42）。然而，我们未观察到宫颈癌风险与rs2234767和rs1800682多态性之间存在任何关联。免疫组织化学分析表明，携带rs763110 TT基因型的患者癌组织中FASL表达低于CC/CT基因型患者。染色质免疫沉淀（ChIP）和序列染色质免疫沉淀分析还表明，OCT1被招募到FASL启动子区域，并通过与C/EBPβ相互作用调节FASL基因转录。总之，本研究提供的证据表明，FASL启动子中的rs763110变异通过影响C/EBPβ/OCT1复合物与染色质的结合亲和力与宫颈癌风险相关。
