Up-regulation of expression of the Ubiquitin Carboxyl-Terminal Hydrolase L1 gene in human airway epithelium of cigarette smokers
Up-regulation of expression of the Ubiquitin Carboxyl-Terminal Hydrolase L1 gene in human airway epithelium of cigarette smokers
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DOI：
10.1158/0008-5472.can-06-2224
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发表时间：
2006-11-15
期刊：
影响因子：
11.2
通讯作者：
Crystal, Ronald G.
中科院分区：
文献类型：
--
作者：
Carolan, Brendan J.;Heguy, Adriana;Crystal, Ronald G.
神经内分泌分化是肺癌的共同特征，慢性吸烟者的神经内分泌细胞及其多肽数量增加。为了了解吸烟对神经内分泌细胞基因表达谱的影响，采用TaqMan确认的微阵列分析评估了81例患者（正常不吸烟者、正常吸烟者、早期慢性阻塞性肺疾病（COPD）吸烟者和已确诊COPD的吸烟者）通过纤维支气管镜获得的气道上皮样本。在11个被认为是神经内分泌细胞特异性的基因中，只有泛素蛋白酶体途径的成员泛素羧基末端水解酶L1 （UCHL1）在吸烟者中与不吸烟者相比持续上调。通过对吸烟者和非吸烟者的支气管活检进行免疫组化分析，可以观察到UCHL1在蛋白水平上的上调。UCHL1仅在非吸烟者气道上皮神经内分泌细胞中有明显表达；然而，UCHL1也在吸烟者的纤毛上皮细胞中表达。这一观察结果可能进一步支持了最近关于纤毛细胞能够向其他气道上皮细胞转分化的观察结果。鉴于UCHL1参与细胞内不需要的、错误折叠的或受损蛋白的降解，并在50%的肺癌中过表达，其在慢性吸烟者中的过表达可能代表了从正常上皮到明显恶性肿瘤复杂转化的早期事件。
Neuroendocrine differentiation is a common feature of lung cancer and increased numbers of neuroendocrine cells and their peptides have been described in chronic smokers. To understand the effects of cigarette smoking on the gene expression profile of neuroendocrine cells, microarray analysis with TaqMan confirmation was used to assess airway epithelial samples obtained by fiberoptic bronchoscopy from 81 individuals [normal nonsmokers, normal smokers, smokers with early chronic obstructive lung disease (COPD), and smokers with established COPD]. Of 11 genes considered to be neuroendocrine cell specific, only ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), a member of the ubiquitin proteasome pathway, was consistently up-regulated in smokers compared with nonsmokers. Up-regulation of UCHL1 at the protein level was observed with immunohistochemical analysis of bronchial biopsies of smokers compared with nonsmokers. UCHL1 expression was evident only in neuroendocrine cells of the airway epithelium in nonsmokers; however, UCHL1 was also expressed in ciliated epithelial cells in smokers. This observation may add further weight to recent observations that ciliated cells are capable of transdifferentiating to other airway epithelial cells. In the context that UCHL1 is involved in the degradation of unwanted, misfolded, or damaged proteins within the cell and is overexpressed in > 50% of lung cancers, its overexpression in chronic smokers may represent an early event in the complex transformation from normal epithelium to overt malignancy.