Abstract
Background
Aberrant expression of interleukin-6 (IL-6) may play an important role in lung carcinogenesis. Whether IL-6 promoter haplotypes are associated with lung cancer risk and their functions have not yet been studied. We tested the hypothesis that single-nucleotide polymorphism (SNP) and/or haplotypes of IL-6 promoter are associated with risk of lung cancer.
Methods
Two functional IL-6 promoter SNPs (-6331T>C and -572C>G) were genotyped in the discovery group including 622 patients and 614 controls, and the results were replicated in an independent validation group including 615 patients and 638 controls. Luciferase reporter gene assays were conducted to examine the function of IL-6 promoter haplotypes.
Results
None of the functional IL-6 promoter SNPs were associated with lung cancer risk in either study. However, a two-SNP CC (-6331C and -572C) IL-6 promoter haplotype was significantly more common among cases than among controls in both groups (P = 0.031 and P = 0.035, respectively), indicating that this haplotype is associated with increased lung cancer risk {adjusted odds ratio [OR], 1.56 [95 % confidence interval (95 % CI), 1.04–2.34] and 1.51 [95 % CI, 1.03–2.22], respectively}. Combined analysis of both studies showed a strong association of this two-SNP haplotype with increased lung cancer risk (adjusted OR, 1.53; 95 % CI, 1.16–2.03; P = 0.003). Comparably, luciferase reporter assays of A549 lung cancer cell lines transfected with the CC haplotype revealed that the two-SNP haplotype had significantly higher IL-6 transcriptional activity compared with cells transfected with the common haplotype.
Conclusions
This is the first evidence of identifying an IL-6 promoter haplotype (CC) associated with increased risk of lung cancer.
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Acknowledgments
This work was supported in part by the grants from National Natural Science Foundation of China (81171894 and 30973425 to H.-T. Zhang), Program for New Century Excellent Talents in University (NCET-09-0165 to H.-T. Zhang), SRF for ROCS, State Education Ministry (2008890 to H.-T. Zhang), Shanghai Science and Technology Research Program (09JC1402200 to D. Lu), Jiangsu Province’s Key Provincial Talents Program (RC2011106 to J. Zhao), Jiangsu Province’s Outstanding Medical Academic Leader Program (LJ201138 to J. He), Qing-Lan Project of Education Bureau of Jiangsu Province (to H.-T. Zhang), “333” Project of Jiangsu Province Government (to H.-T. Zhang), Soochow Scholar Project of Soochow University (to H.-T. Zhang), and Suzhou Key Laboratory for Molecular Cancer Genetics (SZS201209 to H.-T. Zhang).
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The authors declared no conflicts of interest.
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Jun Chen, Reng-Yun Liu, Lixin Yang and Jun Zhao contributed equally to this work.
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Chen, J., Liu, RY., Yang, L. et al. A two-SNP IL-6 promoter haplotype is associated with increased lung cancer risk. J Cancer Res Clin Oncol 139, 231–242 (2013). https://doi.org/10.1007/s00432-012-1314-z
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DOI: https://doi.org/10.1007/s00432-012-1314-z