Vishwanatha Jamboor K, Swinney Ryan, Banerjee Abhijit G
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-4525, USA.
Mol Cell Biochem. 2003 Jun;248(1-2):67-75. doi: 10.1023/a:1024153431272.
Smokeless tobacco usage is a growing public health concern in the United States. Epidemiological evidence shows a correlation between use of chewing tobacco, lesions of the oral cavity and the incidence of oral and other cancers. However, the molecular mechanism(s) underlying the oral cancer causation are yet unknown. The major constituents of tobacco are known to cause inflammation, DNA damage and cell death. We propose modulation of inflammatory mediators by smokeless tobacco as a novel mechanism for the development of oral cancer. Exposure of hamster cheek pouches to smokeless tobacco extract (STE) results in cleavage of the anti-inflammatory peptide from the anti-inflammatory protein annexin I. Annexin I is produced from cultured oral epithelial cells and its expression is modulated by STE. We further show that STE exposure of oral epithelial cells results in upregulation of the pro-inflammatory protein COX-2. COX-2 is also upregulated in immortalized human oral epithelial cells, human squamous cell carcinoma cells and in primary tumor tissues from head and neck cancer. In summary, we find that exposure to smokeless tobacco results in loss of the anti-inflammatory activity of annexin I and upregulation of the pro-inflammatory COX-2 in oral cells. The dual effect of these regulatory events leads the cells down the carcinogenic pathway.
在美国，无烟烟草的使用正日益引起公众对健康的关注。流行病学证据表明，嚼烟的使用、口腔病变与口腔癌及其他癌症的发病率之间存在关联。然而，口腔癌发病的分子机制尚不清楚。已知烟草的主要成分会引发炎症、DNA损伤和细胞死亡。我们提出，无烟烟草对炎症介质的调节作用是口腔癌发生发展的一种新机制。将仓鼠颊囊暴露于无烟烟草提取物（STE）会导致抗炎蛋白膜联蛋白I中的抗炎肽裂解。膜联蛋白I由培养的口腔上皮细胞产生，其表达受STE调节。我们进一步表明，口腔上皮细胞暴露于STE会导致促炎蛋白COX-2上调。在永生化的人口腔上皮细胞、人鳞状细胞癌细胞以及头颈癌的原发性肿瘤组织中，COX-2也会上调。总之，我们发现接触无烟烟草会导致口腔细胞中膜联蛋白I的抗炎活性丧失以及促炎的COX-2上调。这些调节事件的双重作用会使细胞走上致癌途径。
