Functional regulatory variants of MCL1 contribute to enhanced promoter activity and reduced risk of lung cancer in nonsmokers: Implications for context-dependent phenotype of an antiapoptotic and antiproliferative gene in solid tumor

Authors

  • Yan Jiang MS,

    1. State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China
    2. Department of Chemistry, Fudan University, Shanghai, People's Republic of China
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  • Wenjing Wang MD,

    1. Department of Public Health and Molecular Biology, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, People's Republic of China
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  • Jiucun Wang PhD,

    1. State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China
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  • Ye Lu PhD,

    1. Department of Public Health and Molecular Biology, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, People's Republic of China
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  • Yanmei Chen BS,

    1. State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China
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  • Li Jin PhD,

    1. State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China
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  • Dongxin Lin MD,

    Corresponding author
    1. Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
    • Department of Etiology and Carcinogenesis, Cancer Institute, Chinese Academy of Medical Sciences, Beijing 100021, People's Republic of China
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    • Fax: 86-10-67722460

  • Fuchu He PhD,

    Corresponding author
    1. State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China
    2. Department of Chemistry, Fudan University, Shanghai, People's Republic of China
    3. State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of radiation Medicine, Beijing, People's Republic of China
    • School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China
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    • a

      Fax: 86-21-54237158

  • Haijian Wang PhD

    Corresponding author
    1. State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China
    2. The Simons Center for Systems Biology, School of Natural Sciences, Institute for Advanced Study, Princeton, New Jersey
    • School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China
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      Fax: 86-21-54237158


Abstract

BACKGROUND:

Dysfunction of molecules that regulate both apoptosis and proliferation is involved in tumorigenesis. A common insertional polymorphism in promoter of MCL1, a member of BCL2 family gene with the dual regulatory functions, has been shown to be functional in leukemia, but its association with cancer predisposition and prognosis has not been well established. We hypothesized that MCL1 promoter variants may modify risk of solid cancer.

METHODS:

We genotyped −190 insertional polymorphism and 3 linked single nucleotide polymorphisms (SNPs) (−627A>C, −298G>C, and −235C>A) in 320 lung cancer patients and 362 controls, and analyzed their functional significance.

RESULTS:

We confirmed that these regulatory variants correlated with enhanced promoter activity and elevated expression of both mRNA and protein in solid cancer cells and tissues. We further demonstrated that heightened expression of MCL1 resulted in decreased proliferation ability of lung cancer cells. We found a reduced cancer risk (adjusted odds ratio [OR] = 0.47; 95% confidence interval [CI] = 0.25-0.88) associated with −190 insertional genotype. Stratification analysis further showed pronounced associations in nonsmokers (OR, 0.25; 95% CI, 0.09-0.70), in females (OR, 0.22; 95% CI, 0.07-0.74), and in the histological type of adenocarcinoma (OR, 0.18; 95% CI, 0.05-0.62). Likewise, homologous diplotype of these polymorhpisms that positively affected gene expression was associated with reduced risk in nonsmokers (OR, 0.19; 95% CI, 0.06-0.58).

CONCLUSION:

The present study demonstrated that common variants in MCL1 promoter correlated with increased transactivation in solid cancer cells and were associated with reduced risk of lung cancer in nonsmokers, suggesting a dominant antiproliferative function of MCL1 against its antiapoptosis effect in development of solid cancer in nonsmokers. Cancer 2012. © 2011 American Cancer Society.

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