Department of Surgery (Head and Neck Service),Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Cancer Prev Res (Phila). 2010 Mar;3(3):266-78. doi: 10.1158/1940-6207.CAPR-09-0192. Epub 2010 Feb 23.
Use of tobacco is responsible for approximately 30% of all cancer-related deaths in the United States, including cancers of the upper aerodigestive tract. In the current study, 40 current and 40 age- and gender-matched never smokers underwent buccal biopsies to evaluate the effects of smoking on the transcriptome. Microarray analyses were carried out using Affymetrix HGU133 Plus 2 arrays. Smoking altered the expression of numerous genes: 32 genes showed increased expression and 9 genes showed reduced expression in the oral mucosa of smokers versus never smokers. Increases were found in genes involved in xenobiotic metabolism, oxidant stress, eicosanoid synthesis, nicotine signaling, and cell adhesion. Increased numbers of Langerhans cells were found in the oral mucosa of smokers. Interestingly, smoking caused greater induction of aldo-keto reductases, enzymes linked to polycyclic aromatic hydrocarbon-induced genotoxicity, in the oral mucosa of women than men. Striking similarities in expression changes were found in oral compared with the bronchial mucosa. The observed changes in gene expression were compared with known chemical signatures using the Connectivity Map database and suggested that geldanamycin, a heat shock protein 90 inhibitor, might be an antimimetic of tobacco smoke. Consistent with this prediction, geldanamycin caused dose-dependent suppression of tobacco smoke extract-mediated induction of CYP1A1 and CYP1B1 in vitro. Collectively, these results provide new insights into the carcinogenic effects of tobacco smoke, support the potential use of oral epithelium as a surrogate tissue in future lung cancer chemoprevention trials, and illustrate the potential of computational biology to identify chemopreventive agents.
在美国，约有 30%的癌症相关死亡可归因于烟草使用，包括上呼吸道和消化道癌症。在本研究中，40 名现吸烟者和 40 名年龄和性别匹配的从不吸烟者接受了颊黏膜活检，以评估吸烟对转录组的影响。使用 Affymetrix HGU133 Plus 2 阵列进行微阵列分析。吸烟改变了许多基因的表达：与从不吸烟者相比，吸烟者的口腔黏膜中 32 个基因表达增加，9 个基因表达减少。在参与外源性代谢物、氧化应激、类二十烷酸合成、尼古丁信号传导和细胞黏附的基因中发现了增加。吸烟者的口腔黏膜中发现了更多的朗格汉斯细胞。有趣的是，与男性相比，吸烟在女性口腔黏膜中引起更多的醛酮还原酶（与多环芳烃诱导的遗传毒性相关的酶）诱导。与支气管黏膜相比，口腔黏膜中观察到的基因表达变化具有惊人的相似性。使用连接图谱数据库将观察到的基因表达变化与已知的化学特征进行比较，并表明格尔德霉素（一种热休克蛋白 90 抑制剂）可能是烟草烟雾的模拟物。与这一预测一致，格尔德霉素在体外剂量依赖性抑制烟草烟雾提取物介导的 CYP1A1 和 CYP1B1 的诱导。总的来说，这些结果提供了烟草烟雾致癌作用的新见解，支持将口腔上皮作为未来肺癌化学预防试验中的替代组织，并且说明了计算生物学在识别化学预防剂方面的潜力。
