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Genetic variant in CASP3 affects promoter activity and risk of esophageal squamous cell carcinoma.

ABSTRACT: Caspase-3 (CASP3) is the main executioner of apoptosis, mediating both extrinsic and intrinsic cell death signaling pathways, and is involved in tumor behaviors. In this study, we investigated the association of two regulatory variants in CASP3 and the risk of esophageal squamous cell carcinoma (ESCC) in 1026 cases and 1270 healthy controls. Odds ratios (OR) and 95% confidence intervals (CI) were computed by logistic regression. The function of the CASP3 829 A>C polymorphism was examined by luciferase reporter assay and real-time PCR. A significant increased risk of ESCC was found for the CASP3 829 AC and CC genotypes with OR (95% CI), 1.53 (1.26-1.89) and 1.42 (1.11-1.82), respectively. When stratified by age and gender, the risk of ESCC was more significant in younger (?57 years) and male individuals. No significantly changed risk of ESCC was related to 20541 C>T variant. Luciferase reporter assay showed 829 A>C variant dramatically reduced the transcriptional activity of luciferase reporter gene by over 95% in both KYSE30 and KYSE450 esophageal cancer cells. Remarkably, the transcriptional activity of the 829C-containing construct was much lower than the activity of the pGL3-basic construct, with over 85% reduction in both cell lines. Real-time PCR analyses showed that 829 AA genotype carriers had significantly higher RNA levels (0.015 ± 0.00216, n = 24) than the 829 AC genotype carriers (0.00969 ± 0.00136, n = 36), and 829 CC genotype carriers (0.00663 ± 0.00097, n = 20). These findings suggest that CASP3 829 A>C polymorphism may highly affect the function of caspase-3 and play an important role in the development of ESCC in Chinese populations.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC7713629 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Genetic variant in CASP3 affects promoter activity and risk of esophageal squamous cell carcinoma.

Zhang Zhi Z Yu Xinfeng X Guo Yongli Y Song Wenguang W Yu Dianke D Zhang Xuemei X

Cancer science 20120109 3

Caspase-3 (CASP3) is the main executioner of apoptosis, mediating both extrinsic and intrinsic cell death signaling pathways, and is involved in tumor behaviors. In this study, we investigated the association of two regulatory variants in CASP3 and the risk of esophageal squamous cell carcinoma (ESCC) in 1026 cases and 1270 healthy controls. Odds ratios (OR) and 95% confidence intervals (CI) were computed by logistic regression. The function of the CASP3 829 A>C polymorphism was examined by luci ...[more]

PMID: 22136337

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Project description:BackgroundToll-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.MethodsThis 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).ResultsCompared 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.ConclusionThe TLR4 rs1927914 variant contributes to the ESCC risk by effecting the promoter activity.

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.

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Genetic variant in CASP3 affects promoter activity and risk of esophageal squamous cell carcinoma.

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Genetic variant in CASP3 affects promoter activity and risk of esophageal squamous cell carcinoma.

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