Effects of cigarette smoke on the human oral mucosal transcriptome.
Effects of cigarette smoke on the human oral mucosal transcriptome.
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DOI：
10.1158/1940-6207.capr-09-0192
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发表时间：
2010-03
期刊：
影响因子：
--
通讯作者：
Dannenberg AJ
中科院分区：
文献类型：
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作者：
Boyle JO;Gümüs ZH;Kacker A;Choksi VL;Bocker JM;Zhou XK;Yantiss RK;Hughes DB;Du B;Judson BL;Subbaramaiah K;Dannenberg AJ
在美国，烟草的使用导致了大约30%的癌症相关死亡，包括上呼吸消化道癌症。在目前的研究中，40名当前和40名年龄和性别匹配的从不吸烟者接受了颊部活检，以评估吸烟对转录组的影响。微阵列分析使用Affyphase HGU 133 Plus2阵列进行。吸烟改变了许多基因的表达：32个基因的表达增加，9个基因的表达减少，在吸烟者与从不吸烟者的口腔粘膜中。增加被发现在参与异生物质代谢，氧化应激，类花生酸合成，尼古丁信号和细胞粘附的基因。吸烟者口腔粘膜中郎格罕细胞数量增加。有趣的是，吸烟导致更多的诱导醛酮还原酶，酶链接到多环芳烃诱导的遗传毒性，在女性口腔粘膜比男性。与支气管粘膜相比，口腔中的表达变化具有惊人的相似性。使用连接图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Hsp90抑制剂）可能是烟草烟雾的抗模拟物。与这一预测一致，格尔德霉素在体外对烟草烟雾提取物介导的CYP1A1和CYP1B1诱导产生剂量依赖性抑制。总的来说，这些结果为烟草烟雾的致癌作用提供了新的见解，支持口腔上皮在未来肺癌化学预防试验中作为替代组织的潜在用途，并说明了计算生物学识别化学预防剂的潜力。
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 HGU 133 Plus2 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 vs. 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 to the bronchial mucosa. The observed changes in gene expression were compared to known chemical signatures using the Connectivity Map database, and suggested that geldanamycin, an Hsp90 inhibitor, might be an anti-mimetic 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.