P-120 Expression of cyclin D1 in bronchial epithelium of smokers

Abstract

Cyclin Dl synthesis and activity levels peak in Gl, are tightly regulated during other phases of the cell cycle, and are critical in driving cells through the Gl restriction point, committing them to complete the cell cycle. Dysregulated expression of Cyclin Dl has been implicated in lung carcinogenesis. To determine whether altered expression of Cyclin Dl occurs in benign, tobacco-exposed bronchial epithelium as a precursor of invasive lung cancer we studied expression of Cyclin Di in anatomically mapped regions of proximal bronchus in 66 smokers undergoing lung resections mostly for primary lung cancer. Relative expression of Cyclin 01 by Taqman real-time PCR analysis was high i.e. >I000 fold arbitrary reference levels in at least one epithelial region (two to seven separate epithelial regions analysed per patient) in 18 of 66 current or ex-smokers (27%) and 0 of 6 never smokers. Morphological evaluation of flanking transverse sections available in 15 smokers with high levels of Cyclin Dl expression showed normal histology in 9 cases, metaplastic epithelium in 3, and dysplastic epithelium in 3 cases. In most patients high level expression was observed in only one of several epithelial segments analysed, however in one smoker with lung cancer all 3 segments expressed high levels of Cyclin Dl and multiple flanking sections were dysplastic in this case. There was no association between relative expression of Cyclin Dl in bronchial epithelium and genotype at the polymorphic locus A870G in exon 4 of CCNDI in these smokers. We have demonstrated that Cyclin Dl expression is focally high in the bronchial epithelium of a proportion of smokers undergoing lung resections, and that this is more likely related to local conditions in the respiratory tract than to genotypic determinants. Some areas of morphologically normal non-inflamed bronchus express high levels of Cyclin Dl and the altered expression in these cases may accompany focally increased cell turnover in otherwise normal epithelium. To determine the significance of this we plan to extend these studies by correlating bronchial Cyclin Di expression with proliferative indices.