【作者】 吴勇；

【导师】 刘国津；

【作者基本信息】 吉林大学 ， 外科学， 2010， 博士

【摘要】 肺癌,特别是非小细胞肺癌发病率和死亡率正在迅速上升,而且是世界性趋势,已成为恶性肿瘤引起死亡的首要原因。目前仍缺乏有效的用于肺癌诊断和预后监测的特异性分子标志物。因此,寻找敏感性高、特异性好的肺癌分子标志物已成为肺癌研究的一个关键。随着后基因组时代的来临,从基因水平向蛋白质水平的深化也是医学研究发展的必然趋势。通过比较疾病状态与正常生理状态蛋白质表达的差异,发现和鉴定与疾病特异相关的蛋白质,也是肿瘤研究领域里的经典思路。蛋白质的磷酸化修饰调节贯穿了几乎所有的生命活动过程,因此磷酸化蛋白的研究对于理解机体的生命活动也是十分必要的。当正常细胞中蛋白磷酸化调控出现异常时,常常会引起恶性肿瘤,研究磷酸化蛋白质差异,能更好的揭示肿瘤发生机制。本实验根据这一思路,利用pathway array方法对39例非小细胞肺癌患者的癌组织及正常肺组织进行了差异蛋白的筛选,发现了5种磷酸化蛋白(p-ERK、p-CREB、p-p38、p-PDK1、p-cdc2)有异常表达,并采用了组织芯片技术及免疫组织化学方法检测了94例非小细胞肺癌患者的癌组织和肺良性肿瘤组织中CREB/p-CREB的表达情况,进一步探讨了CREB/p-CREB的表达与非小细胞肺癌患者的临床病理因素和预后的关系,为肺癌的发生机制及防治研究提供了新的线索。更多还原

【Abstract】 It is increasing rapidly in the mortality and morbidity of lung cancer, especially the non-small cell lung cancer(NSCLC). It is a worldwide tendency, and, it has become the first etiological factor of malignant carcinomas. So far, it still lack of a specific biomarker for early diagnosis and monitoring prognosis. So it is crucial to find a biomarker for lung cancer with high sensitivity and specificity. With the coming of post-genome period, proteomics with its special thinking method and technology which analyze the alteration of intracellular protein shows its great power to solve biological problems, and it attracts more and more researchers’attention. It have become a kind of classic thread to deal with the research of tumors that with the comparison between morbid and normality, or among different stages of lung cancer, then finding and identifing some kinds of protein that have specific relationship with the disease. According to this thread, this research made a protein-difference screening to the NSCLC tissues and normal ones with the pathway array, that we examined the difference of the expression of CREB/p-CREB between the patients of NSCLC and benefit tumors with the technic of Tissue Microarray (TMA)and immunohistochemistry (IHC). Then we made a further approach to the relationship between the expression of CREB/p-CREB and TMA as long as IHC in clinical pathogen factors and prognosis. These has provided a new clue to do the research in the development, prevention and cure of the lung cancer.Objective: To screen the protein that express differently between NSCLC and normal tissue, and make an advance research in the relationship between CREB/p-CREB and clinical pathogen factors and prognosis of lung cancer patients.Methods: Choose 39 cases of malignant tissue in lung cancer and pairing adjacent normal tissue. Examine the expression in the wax samples of 94 cases of NSCLC and 19 cases of benefit tumors, by using pathway array, aiming at CREB/p-CREB. Make an advance approach to the relationship between CREB/p-CREB and clinical pathogen factors and prognosis of lung cancer patients.Result:1.We have screen out 5 kind of protein with different expression, they are p-PDK1,p-ERK,p-CREB,p-cdc2,p-p38.2.The over expression of CREB in NSCLC was significantly higher than in benign tumor of lung(60% vs 5%, P=0.000); the over expression of P-CREB in NSCLC was non- significantly higher than in benign tumor of lung(46%vs37%, P>0.05)3.The over expression of CREB in squamous carcinoma was significantly higher than in adenocarcinoma(P=0.000); the over expression of CREB in smokers was significantly higher than in non-smokers( P=0.013); but they were both not related to gender, age, tumor size, node status, and TNM stage.4.Survival analysis showed that the survival of lower-expression of CREB was better than the over-expression in adenocarcinoma patients(P=0.034).Conclusion1 p-PDK1,p-ERK,p-CREB,p-Cdc2,p-P38 express differently in normal lung tissues.2 CREB/P-CREB express in nuclear; CREB has an significant higer over-expression in NSCLC tissues, and relate to the attribute of pathogen as long as smoking.3 The survival was worse in lung adenocarcinoma patients with over-expression of CREB.更多还原