Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/Ref-1) is a ubiquitous multifunctional protein that possesses both DNA-repair and redox regulatory activities. Although it was originally identified as a DNA-repair enzyme, accumulating evidence supports a role of APE1/Ref-1 in tumor development. To investigate association between APE1/Ref-1 polymorphisms and lung cancer risk in Chinese populations, we first genotyped three variants of APE1/Ref-1 and found a -141 T-to-G variant (rs1760944) in the promoter associated with decreased risk of lung cancer [ odds ratio ( OR) = 0.62 for GG; P = 0.043]. Similar results were obtained in a follow-up replication study. Combined data from the two studies comprising a total of 1072 lung cancer patients and 1064 cancer-free control participants generated a more significant association ( P = 0.002). We observed lower APE1/Ref-1 mRNA levels in the presence of the protective G allele in human peripheral blood mononuclear cells and normal lung tissues. The -141G-allele-promoter construct exhibited decreased luciferase reporter gene expression. Electrophoretic mobility shift assays and surface plasmon resonance analysis showed that the -141G allele impaired the binding affinity of some transcription factor, accounting for lower APE1/Ref-1-promoter activity. Supershift assays further revealed that the protein of interest was octamer-binding transcription factor-1 (Oct-1). Chromatin immunoprecipitation reconfirmed binding of Oct-1 to the APE1/Ref-1 -141-promoter region. We also found that Oct-1 conferred attenuated transactivation capacity toward the -141G variant by exogenously introducing Oct-1. These data indicate that genetic variations in APE1/Ref-1 may modify susceptibility to lung cancer and provide new insights into an unexpected effect of APE1/Ref-1 on lung carcinogenesis.-Lu, J., Zhang, S., Chen, D., Wang, H., Wu, W., Wang, X., Lei, Y., Wang, J., Qian, J., Fan, W., Hu, Z., Jin, L., Shen, H., Huang, W., Wei, Q., Lu, D. Functional characterization of a promoter polymorphism in APE1/Ref-1 that contributes to reduced lung cancer susceptibility. FASEB J. 23, 3459-3469 ( 2009). www.fasebj.org
[1]Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China.
[2]Fudan Univ, Sch Life Sci, Minist Educ, Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China.
[3]Harbin Med Coll, Clin Med Sch 1, Brain Tumor Res Ctr, Dept Neurol Surg, Harbin, Peoples R China.
[4]Nanjing Med Univ, Canc Res Ctr, Dept Epidemiol & Biostat, Nanjing, Peoples R China.
[5]Chinese Natl Human Genome Ctr, Dept Genet, Shanghai, Peoples R China.
[6]Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA.
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