Dataset Information

TLR4 promoter rs1927914 variant contributes to the susceptibility of esophageal squamous cell carcinoma in the Chinese population.

ABSTRACT:

Background

Toll-like receptor 4 (TLR4), as a key regulator of both innate and acquired immunity, has been linked with the development of various cancers, including esophageal cancer. This study aims to analyze the association of potential functional genetic polymorphisms in TLR4 with the risk of esophageal cancer.

Methods

This case-control study involved in 480 ESCC patients and 480 health controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to genotype TLR4 rs1927914 polymorphism. Taqman probe method was used to determine the genotypes of TLR4 rs11536891 and rs7873784 variants. The relationship between TLR4 genetic variation and ESCC risk was analyzed by Logistic regression model by calculating the odds ratio (OR) and 95% confidence interval (95% CI).

Results

Compared with TLR4 rs1927914 AA genotype carriers, GG carriers had a lower ESCC risk (OR = 0.59, 95% CI [0.38-0.93], P = 0.023). Stratification analysis by age showed that TLR4 rs1927914 GG could affect the risk of ESCC in elderly people (OR = 0.59, 95% CI [0.36-0.97]). Smoking stratification analysis indicated that rs1927914 GG carriers were related to ESCC susceptibility among non-smokers (OR = 0.36, 95% CI [0.18-0.73]). Dual luciferase reporter assay suggested that rs1927914 G-containing TLR4 promoter displayed a 1.76-fold higher luciferase activity than rs1927914 A-containing counterpart in KYSE30 cells. Electrophoretic mobility shift assay (EMSA) showed the KYSE30 cell nuclear extract was able to bind the probe with rs1927914 G allele and this DNA-protein interaction could be eliminated by competition assays with unlabeled rs1927914 G probe, which indicating that the binding is sequence-specific. Our results also showed that TLR4 rs7873784 (G>C) and rs11536891 (T>C) conformed to complete genetic linkage. The genotype distributions of TLR4 rs11536891 variant among ESCC patients and normal controls have no statistical significance.

Conclusion

The TLR4 rs1927914 variant contributes to the ESCC risk by effecting the promoter activity.

SUBMITTER: Li J

PROVIDER: S-EPMC7860108 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

TLR4 promoter rs1927914 variant contributes to the susceptibility of esophageal squamous cell carcinoma in the Chinese population.

Li Jiaying J Wu Hongjiao H Gao Hui H Kou Ruihuan R Xie Yuning Y Zhang Zhi Z Zhang Xuemei X

PeerJ 20210201

<h4>Background</h4>Toll-like receptor 4 (TLR4), as a key regulator of both innate and acquired immunity, has been linked with the development of various cancers, including esophageal cancer. This study aims to analyze the association of potential functional genetic polymorphisms in TLR4 with the risk of esophageal cancer.<h4>Methods</h4>This case-control study involved in 480 ESCC patients and 480 health controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was ...[more]

PMID: 33585082

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Project description:BackgroundSingle nucleotide polymorphisms (SNPs) located in microRNA (miRNA) binding sites can affect the interactions between miRNAs and target genes, which is related to cancer susceptibility and tumorigenesis. However, the association between SNPs located in miR-17-92 cluster binding sites and ESCC risk remains unclear. Therefore, we aimed to explore the relationship between polymorphisms in miR-17-92 cluster binding sites and ESCC susceptibility.MethodsSix SNPs in the binding sites of miR-17-92 cluster were selected using bioinformatics databases, and their association with ESCC risk was investigated in a case-control study (including 488 cases and 512 controls) based on the population from high incidence areas of ESCC in China. We evaluated the SNP-SNP and SNP-smoking interactions using generalized multifactor dimensionality reduction (GMDR). Moreover, the expression of the miR-17-92 cluster and its target genes was determined in ESCC and adjacent normal tissues by quantitative real-time polymerase chain reaction (qRT-PCR). The dual-luciferase reporter assay was conducted to verify the effect of SNPs on the binding affinity between miRNAs and target genes.ResultsWe found that the SNP rs1804506 C > T had a significant association with the decreased ESCC risk. The SNP rs1804506 T allele was associated with a significantly decreased risk of ESCC in the additive model (OR = 0.817, 95% CI = 0.681-0.981, P = 0.030). The rs1804506 T allele had more striking effects on reducing ESCC risk in older individuals, female or non-smoker subgroups. We also found a significant interaction effect between rs1366600 and smoking by GMDR methods (P = 0.011). Additionally, the expression levels of miR-19a-3p and TGFBR3 were significantly downregulated in ESCC tissues compared with normal tissues, and the carriers of rs1804506 TT genotype had lower expression level of TGFBR3 than those of rs1804506 CC/CT genotype. Following dual-luciferase reporter assay showed that the rs1804506 T allele reduced the binding of miR-19a-3p and TGFBR3 3'-UTR.ConclusionsOur findings suggest that the rs1804506 polymorphism in miR-17-92 cluster binding sites contributes to the susceptibility of ESCC, which might provide new clues and scientific evidence for the etiology and biomarkers for the prevention and treatment of ESCC.

Project description:BackgroundThe human 5p15.33 locus contains two well-known genes, the telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) genes, which have been implicated in carcinogenesis. A common sequence variant, rs401681, located in an intronic region of CLPTM1L, has been reported to be associated with lung cancer risk based on genome-wide association study. However, subsequent replication studies in diverse populations have yielded inconsistent results. In addition, genetic variants at 5p15.33, including rs401681, have been shown to be involved in the susceptibility to multiple malignancies. Nevertheless, the role of these TERT-CLPTM1L variants in the etiology of esophageal squamous cell carcinoma (ESCC) remains unknown.MethodsWe genotyped the rs401681 polymorphism using TaqMan methodology and analyzed its association with the risk of lung cancer and ESCC in a case-control study of 1,479 cancer patients (726 with lung cancer and 753 with ESCC) and 860 healthy individuals.ResultsLogistic regression analyses revealed that rs401681 T genotypes were associated with a significantly decreased risk of lung cancer (CT vs. CC: adjusted OR=0.782, 95% CI=0.625-0.978, P=0.031; CT/TT vs. CC: adjusted OR=0.786; 95% CI=0.635-0.972, P=0.026). Stratification analysis by histology type indicated that rs401681 T genotypes were associated with a significantly reduced risk of both adenocarcinoma and squamous cell carcinoma. Furthermore, no significant association was observed between rs401681 and the risk of ESCC (CT vs. CC: adjusted OR=0.910, 95% CI=0.734-1.129, P=0.392; TT vs. CC: adjusted OR=0.897, 95%CI=0.624-1.290, P=0.558; CT/TT vs. CC: adjusted OR=0.908, 95% CI=0.740-1.114, P=0.355).ConclusionsOur findings provide further evidence supporting rs401681 as a genetic variant associated with the risk of lung cancer. In addition, we investigated the correlation between the rs401681 variant and the risk of ESCC in a Han Chinese population, and our results suggest that this genetic variant may not be involved in ESCC risk.

Dataset Information

TLR4 promoter rs1927914 variant contributes to the susceptibility of esophageal squamous cell carcinoma in the Chinese population.

Background

Methods

Results

Conclusion

Publications

TLR4 promoter rs1927914 variant contributes to the susceptibility of esophageal squamous cell carcinoma in the Chinese population.

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