Section of Computational Biomedicine, Department of Medicine, Boston University Medical Center; Bioinformatics Program, Boston University, Boston, Massachusetts, USA.
Cancer Res. 2012 Nov 15;72(22):5702-11. doi: 10.1158/0008-5472.CAN-12-1043. Epub 2012 Sep 17.
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.
香烟烟雾会在呼吸道上皮细胞中产生损伤的分子场。然而，吸烟者气道中改变的特定信号通路以及导致从吸烟引起的气道损伤到肺癌的转变的信号过程仍然未知。在这项研究中，我们使用基因组方法研究与烟草烟雾暴露和肺癌相关的信号过程。首先，我们开发并验证了支气管气道上皮细胞中反映与烟草暴露相关的信号通路激活的通路特异性基因表达特征，包括 ATM、BCL2、GPX1、NOS2、IKBKB 和 SIRT1。使用这些图谱和四个独立的基因表达数据集，我们发现与不吸烟者相比，活跃吸烟者的细胞学正常支气管气道上皮细胞中的 SIRT1 活性显着上调。相比之下，这种活性在非小细胞肺癌中明显下调。这种信号调节模式是 SIRT1 所特有的，并且 SIRT1 活性的下调仅限于吸烟者的肿瘤。使用肺癌小鼠模型的基因组分析和对患者肺肿瘤中 SIRT1 活性的生化测试验证了 SIRT1 活性的降低。总之，我们的发现表明 SIRT1 在对烟雾的反应中起作用，并可能在抑制肺癌中起作用。此外，我们的发现表明，本研究中得出的气道基因表达特征可以为烟草烟雾引起的“损伤场”中改变的信号通路提供新的见解，从而可能影响预防与烟草相关的肺癌的策略。
