title: SIRT1 pathway dysregulation in the smoke-exposed airway epithelium and lung tumor tissue.
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 upregulated in cytologically normal bronchial airway epithelial cells from active smokers compared with nonsmokers. In contrast, this activity is strikingly downregulated in non-small cell lung cancer. This pattern of signaling modulation was unique to SIRT1, and downregulation 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. Furthermore, 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 injury" induced by tobacco smoke and thus may impact strategies for prevention of tobacco-related lung cancer.
authors.affiliation: Section of Computational Biomedicine, Department of Medicine, Boston University Medical Center; Bioinformatics Program, Boston University, Boston, Massachusetts, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Beane
authors.forename: Luis
authors.initials: L
authors.lastname: Cheng
authors.forename: Raffaella
authors.initials: R
authors.lastname: Soldi
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Christina
authors.initials: C
authors.lastname: Anderlind
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lenburg
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
authors.forename: Andrea H
authors.initials: AH
authors.lastname: Bild
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics* / Q000378:metabolism; D012907:Smoking / Q000235:genetics* / Q000378:metabolism
chemical_list: C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1