Journal Article

A functional variant (−1304T>G) in the <i>MKK4</i> promoter contributes to a decreased risk of lung cancer by increasing the promoter activity

Bin Liu, Dianke Chen, Lei Yang, Yinyan Li, Xiaoxuan Ling, Lin Liu, Weidong Ji, Yisheng Wei, Jianping Wang, Qingyi Wei, Lei Wang and Jiachun Lu

in Carcinogenesis

Volume 31, issue 8, pages 1405-1411
Published in print August 2010 | ISSN: 0143-3334
Published online June 2010 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgq126
A functional variant (−1304T>G) in the MKK4 promoter contributes to a decreased risk of lung cancer by increasing the promoter activity

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Mitogen-activated protein kinase kinase 4 (MKK4) is a critical mediator of stress-activated protein kinase signals that regulate apoptosis, inflammations and tumorigenesis. Several polymorphisms have been identified in the MKK4 gene. We hypothesized that genetic variants in the MKK4 promoter may alter its expression and thus cancer risk. In a case–control study of 1056 lung cancer cases and 1056 sex and age frequency-matched cancer-free controls, we genotyped two common polymorphisms in the MKK4 promoter region (−1304T>G and −1044A>T) with the Taqman assay, and we found that compared with the most common −1304TT genotype, carriers of −1304G variant genotypes had a decreased risk of lung cancer [odds ratio (OR) = 0.74; 95% confidence interval (CI) = 0.61–0.90 for TG, and OR = 0.62; 95% CI = 0.41–0.94 for GG] in an allele dose–response manner (adjusted Ptrend = 0.0005). Further stratification analysis showed that the protective role of the −1304G variant allele was more evident in low or normal body mass index (BMI) but restrained in the overweighters and that the −1304G variant genotypes interacted with BMI in reducing cancer risk (adjusted Pinteraction  = 0.003). Moreover, the luciferase assay showed that the G allele in the promoter significantly increased the transcription activity of the MKK4 gene in vitro and that the MKK4 protein expression levels of the G variant carriers was significantly higher in tumor tissues than those of the −1304TT genotype. However, no significant association was observed between the −1044A>T polymorphism and risk of lung cancer. Our data suggest that the functional −1304G variant in the MKK4 promoter contributes to a decreased risk of lung cancer by increasing the promoter activity and that the G variant may be a marker for susceptibility to lung cancer.

Journal Article.  5267 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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