Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fuzhou, China.
Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China.
Cancer Med. 2018 May;7(5):2211-2218. doi: 10.1002/cam4.1453. Epub 2018 Apr 10.
Genetic variations of NF-κB and its inhibitor IκB genes and their biological mechanism in oral cancer were not well recognized. The purpose of this study was to evaluate the associations of polymorphisms in NFKB1 and NFKBIA with oral cancer susceptibility, and further explore their potential mechanism in vitro. First, the polymorphisms of NFKB1 and NFKBIA were genotyped through iPLEX Sequenom MassARRAY platform in a case-control study with 425 oral cancer patients and 485 healthy controls. Then, the function was explored by a luciferase reporter assay and an electrophoretic mobility shift assay (EMSA) in human tongue squamous cell carcinoma cell lines. The results indicated that NFKB1 rs28362491 Del/Del and rs72696119 G/G genotypes were associated with the risk of oral cancer, with a strong linkage disequilibrium (D' = 0.991, r = 0.971). Moreover, DG haplotype of NFKB1 also showed a significant increased risk (OR = 1.25, 95% CI: 1.02-1.53, P = 0.030). Dual-luciferase reporter assays further revealed that the plasmids with DG or IG or DC haplotype transfected with Tca-8113 cells or CAL-27 cells had a lower luciferase expression than that with IC haplotype. EMSA demonstrated that 4-bp ATTG deletion in the promoter of NFKB1 abolished the binding site of transcription factor. Our preliminary findings suggest that the haplotype of rs28362491 and rs72696119 in NFKB1 could act as a novel genetic marker to predict oral cancer risk in the southeast of China, but much more extensive researches still need to be conducted.
NF-κB 及其抑制剂 IκB 基因的遗传变异及其在口腔癌中的生物学机制尚不清楚。本研究旨在评估 NFKB1 和 NFKBIA 多态性与口腔癌易感性的关系，并进一步探讨其在体外的潜在机制。首先，通过 iPLEX Sequenom MassARRAY 平台对 425 例口腔癌患者和 485 例健康对照者的 NFKB1 和 NFKBIA 多态性进行基因分型。然后，在人舌鳞癌细胞系中通过荧光素酶报告基因检测和电泳迁移率变动分析（EMSA）来探索其功能。结果表明，NFKB1 rs28362491 Del/Del 和 rs72696119 G/G 基因型与口腔癌的发病风险相关，具有很强的连锁不平衡（D'=0.991，r=0.971）。此外，NFKB1 的 DG 单倍型也显示出显著增加的风险（OR=1.25，95%CI：1.02-1.53，P=0.030）。双荧光素酶报告基因检测进一步表明，与 IC 单倍型相比，转染 Tca-8113 细胞或 CAL-27 细胞的 DG 或 IG 或 DC 单倍型质粒的荧光素酶表达较低。EMSA 表明，NFKB1 启动子中 4-bp ATTG 缺失消除了转录因子的结合位点。我们的初步研究结果表明，NFKB1 的 rs28362491 和 rs72696119 单倍型可能作为一种新的遗传标志物，用于预测中国东南部地区口腔癌的发病风险，但仍需要进行更广泛的研究。
