8-羟基-脱氧鸟苷在肺癌发生和人支气管上皮细胞癌变过程中的作用

The role of 8-hydroxydeoxyguanine in the development of human lung cancer and in the carcinogenesis of human bronchial epithelial cells

目的 探讨 8 羟基 脱氧鸟苷 (8 OH dG)在肺癌发生中的作用及其分子机制。方法 使用鼠抗人 8 OH dG单克隆抗体 ,检测 15 0例肺癌、12 0例癌旁肺组织、4 0例肺良性病变和 4 0例正常肺组织中 8 OH dG的含量 ;同时检测相应肺组织中P5 3、C MYC、K RAS、BCL 2等癌变相关基因的表达 ,分析 8 OH dG与上述癌变相关基因表达的关系 ;并利用苯并 (a)芘代谢产物B(a)P 二醇 环氧化物 (BPDE)和结晶型硫化镍 (NiS)诱导的体外人支气管上皮细胞转化癌变模型 ,检测癌变进程中 8 OH dG的变化。结果 肺癌组织、癌旁肺组织、肺良性病变和正常肺组织中氧化损伤标志物 8 OH dG的阳性率分别为 92 .7% (139/ 15 0 )、17.5 % (2 1/ 12 0 )、10 .0 % (4 / 4 0 )和 5 .0 % (2 / 4 0 ) ,肺癌组织中 8 OH dG水平高于其它肺组织 (P <0 .0 1)。将肺癌病例按性别、年龄、细胞类型和吸烟史分层分析 ,结果显示它们与 8 OH dG均无关联。分析 8 OH dG与癌变相关基因的关系 ,发现肺癌组织K RAS、Bcl 2基因的过度表达与 8 OH dG含量高有关 ,而P5 3和C MYC基因的表达与 8 OH dG的含量无关联。在体外用BPDE和NiS作用于人支气管上皮细胞系诱导其转化和癌变过程中 ,8 OH dG出现于细胞转化之前 ,其含量的增加与细胞癌变进程相一致。结论 8

Objective To investigate the role of 8-hydroxydeoxyguanine(8-OH-dG) in the development of human lung cancer and its molecular mechanism of carcinogenesis. Methods The content of 8-OH-dG was detected in 150 cases of lung cancer, 120 cases of adjacent lung tissue, 40 cases of benign lung lesions and 40 normal lung tissues, with mouse anti-human 8-OH-dG-specific monoclonal antibody. The expressions of P53, C-MYC, K-RAS and BCL-2 in lung tissues were assessed by immunohistochemistry, which relationship with 8-OH-dG was analyzed. The changes of 8-OH-dG in the progress of carcinogenesis were detected in human bronchial epithelial cells induced by Benzo(a)pyrene diol-epoxide(BPDE)and sulfide nickel(NiS) in vitro. Results The positive rates of 8-OH-dG were 92.7%(139/150), 17.5%(21/120), 10.0%(4/40) and 5.0%(2/40), respectively, in lung cancer tissue, adjacent lung tissues, benign lung lesions and normal lung tissues, which were higher in lung cancer tissue than that in other tissues(P<0.01). There was no relation between sex, age, cell type and history of smoking with 8-OH-dG according to stratification, but the high contents of 8-OH-dG were related with the overexpression of K-RAS and BCL-2 of lung cancer tissue, which was not related with the gene expression of P53 and C-MYC. The content increase of 8-OH-dG was in accordance with the progress of cell carcinogenesis, which was displayed in human bronchial epithelial cells induced by BPDE and NiS. Conclusion 8-OH-dG plays an important role in the induction of lung carcinogenesis, which may be related with the gene changes of K-RAS and BCL-2.