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Research Article

SIRT1 pathway dysregulation in the smoke-exposed airway epithelium and lung tumor tissue

Jennifer Beane, Luis Cheng, Raffaella Soldi, Xiaohui Zhang, Gang Liu, Christina Anderlind, Marc E. Lenburg, Avrum Spira and Andrea Bild
Jennifer Beane
1Medicine, Section of Computational Biomedicine, Boston Univ. School of Medicine
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Luis Cheng
2Dept. Pharmacology and Toxicology, U. Utah
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Raffaella Soldi
2Dept. Pharmacology and Toxicology, U. Utah
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Xiaohui Zhang
3The Pulmonary Center, Boston University Medical Center
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Gang Liu
3The Pulmonary Center, Boston University Medical Center
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Christina Anderlind
4Medicine, Boston University
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Marc E. Lenburg
5Medicine, Section of Computational Biomedicine, Boston University School of Medicine
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Avrum Spira
6Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine
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Andrea Bild
7Pharmacology and Toxicology, University of Utah
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DOI: 10.1158/0008-5472.CAN-12-1043
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Abstract

Cigarette smoke produces a molecular "field of injury" in epithelial cells lining the respiratory tract. However, the specific signaling pathways that are altered in the airway of smokers and the signaling processes responsible for the transition from smoking-induced airway damage to lung cancer remain unknown. In this study, we use a genomic approach to study the signaling processes associated with tobacco smoke exposure and lung cancer. First, we developed and validated pathway-specific gene expression signatures in bronchial airway epithelium that reflect activation of signaling pathways relevant to tobacco-exposure including ATM, BCL2, GPX1, NOS2, IKBKB, and SIRT1. Using these profiles and four independent gene expression datasets, we found that SIRT1 activity is significantly up-regulated in cytologically normal airway epithelial cells from active smokers compared to non-smokers. In contrast, this activity is strikingly down-regulated in non-small cell lung cancer. This pattern of signaling modulation was unique to SIRT1, and down-regulation of SIRT1 activity is confined to tumors from smokers. Decreased activity of SIRT1 was validated using genomic analyses of mouse models of lung cancer and biochemical testing of SIRT1 activity in patient lung tumors. Together, our findings indicate a role of SIRT1 in response to smoke and a potential role in repressing lung cancer. Further, our findings suggest that the airway gene-expression signatures derived in this study can provide novel insights into signaling pathways altered in the "field of inury" induced by tobacco smoke and thus may impact strategies for prevention of tobacco-related lung cancer.

  • Received March 20, 2012.
  • Revision received August 1, 2012.
  • Accepted September 1, 2012.
  • Copyright © 2012, American Association for Cancer Research.
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Published OnlineFirst September 17, 2012
doi: 10.1158/0008-5472.CAN-12-1043

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SIRT1 pathway dysregulation in the smoke-exposed airway epithelium and lung tumor tissue
Jennifer Beane, Luis Cheng, Raffaella Soldi, Xiaohui Zhang, Gang Liu, Christina Anderlind, Marc E. Lenburg, Avrum Spira and Andrea Bild
Cancer Res September 17 2012 DOI: 10.1158/0008-5472.CAN-12-1043

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SIRT1 pathway dysregulation in the smoke-exposed airway epithelium and lung tumor tissue
Jennifer Beane, Luis Cheng, Raffaella Soldi, Xiaohui Zhang, Gang Liu, Christina Anderlind, Marc E. Lenburg, Avrum Spira and Andrea Bild
Cancer Res September 17 2012 DOI: 10.1158/0008-5472.CAN-12-1043
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Cancer Research Online ISSN: 1538-7445
Cancer Research Print ISSN: 0008-5472
Journal of Cancer Research ISSN: 0099-7013
American Journal of Cancer ISSN: 0099-7374

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