A functional haplotype of NFKB1 influence susceptibility to oral cancer: a population‐based and in vitro study

Abstract

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 2 = 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.

Gene Combination of CD44 rs187116, CD133 rs2240688, NF-κB1 rs28362491 and GSTM1 Deletion as a Potential Biomarker in Risk Prediction of Breast Cancer in Lower Northern Thailand

“…This study showed that the *2*2 homozygous genotype (del/del) was associated with a 2 -fold increased risk (p = 0.041) and with the *2 allele was 1.36 increased risk (p = 0.046). This finding is consistent with a previous report that this polymorphism was not only associated with the risk of oral cancer (Chen et al, 2018b), but also with the development of gastric cancer and colorectal cancer (Cavalcante et al, 2017). GSTM1, one of the glutathione-S-transferase gene family, produces the GSTM1 enzyme involved in the detoxification of polycyclic aromatic hydrocarbons and other carcinogens (Strange and Fryer, 1999).…”

“…The group of detoxification genes (GSTM1 and GSTT1) and an inflammatory gene (NF-κB1) are related to tumor-promoting inflammation, while the growth factor genes (TGFβ2 and VEGF) are related to inducing angiogenesis and sustaining proliferative signaling. The (Chen et al, 2018b;Zhou et al, 2009), and several genetic variations are associated with the risk of oral, esophageal, gastric, and colorectal cancers (Lo et al, 2009;Umar et al, 2013;Song et al, 2013;Chen et al, 2018b). The 4-bp ATTG deletion in the promoter of NF-κB1 rs28362491 resulted in the loss of binding to nuclear proteins that reduced promotor activity, hence decreased NF-κB1transcription, and protein production (Karban et al, 2004;Zhou et al, 2009).…”

Genetic Association betweenNFKBIAandNFKB1Gene Polymorphisms and the Susceptibility to Head and Neck Cancer: A Meta-Analysis

“…Nine case-control studies from eight included articles [25, 29–35] were correlated with rs28362491 polymorphism. Among the eight studies, four studies [25, 30, 34, 35] were related to rs2233406 polymorphism. Overall, the meta-analysis included three OC articles, three nasopharyngeal carcinoma (NC) articles, and two HNC articles.…”

NFKB1 gene rs28362491 polymorphism is associated with the susceptibility of acute coronary syndrome

“…They also found that the I allele promoter had significantly higher activity than the D allele and homozygous II genotype cells had higher p50 expression levels than homozygous DD genotype cells. Moreover, Chen F [23] reported that the -94delATTG allele promoter of NFKB1 abolished the binding site of transcription factor and it may increase the susceptibility to oral cancer.…”