胰腺癌基因表达谱整合分析

发布时间：2018-03-29 02:07

本文选题：胰腺导管腺癌　切入点：表达谱数据库　出处：《北京协和医学院》2017年博士论文

【摘要】：背景:胰腺导管腺癌约占所有胰腺肿瘤的90%,是一种难治性恶性肿瘤。由于胰腺癌在早期缺乏特定的症状和体征,早期诊断较困难。由于其复杂的解剖特征和神经侵袭的独特特征,胰腺癌手术切除困难。此外,胰腺导管腺癌对放疗和化疗不敏感。因此,胰腺癌患者预后极差。胰腺癌的发病率和死亡率在世界上仍不断增加。为了提高胰腺癌的诊断及改善预后,迫切需要开发用于胰腺癌早期诊断和有效治疗的分子靶点。随着生物技术的发展,高通量检测基因表达的方法不断更新。DNA微阵列技术和二代测序技术为研究胰腺癌组织及正常组织中差异表达基因提供了简便高效的方法。目的:为了探索胰腺癌发生和进展的分子机制,本研究利用GEO数据库中的微阵列数据挖掘胰腺癌组织与正常胰腺组织中的重要差异表达基因,为胰腺癌的早期诊断及临床治疗提供理论依据。方法:从GEO数据库中下载胰腺癌基因表达谱芯片数据,对胰腺癌组织和癌旁组织差异表达基因进行分析。差异表达的标准为差异倍数大于2且P值小于0.05。利用差异表达基因进行显著性信号通路富集,并以此构建信号通路网络拓扑结构图,在网络拓扑图中找到核心信号通路,并对此通路的差异表达基因与胰腺癌患者的生存进行分析。结果:我们在六组胰腺癌GEO表达谱数据中获得32个共同的显著性信号通路以及13个共同的核心信号通路。癌症信号通路是13个核心信号通路中最重要的信号通路。癌症信号通路在六组数据库中共包含有137个差异表达基因,其中BIRC5、C/KS2、ITGA3、ITGA6和RAL 基因在 TCGA 以及 ICGC 数据库中同时显示基因高表达胰腺癌患者生存时间短于基因低表达患者。其中CKS2的表达水平与基因拷贝数呈正相关,与甲基化程度呈负相关。细胞实验表明,降低CKS2的表达能够抑制BxPC3和CFPAC1细胞的增殖。结论:通过构建信号转导网络拓扑图发现癌症信号通路在胰腺癌发生发展过程中发挥重要的作用,该通路中的CKS2基因促进胰腺癌细胞的增殖,对于CKS2在胰腺癌中的分子机制研究对于阐明胰腺癌发生发展机制具有重要作用。
[Abstract]:Background: pancreatic ductal adenocarcinoma accounted for about 90% of all pancreatic tumors, is a kind of refractory malignant tumor. Because of pancreatic cancer in the absence of specific symptoms and signs of early, early diagnosis is difficult. Because of its unique anatomical features and complex characteristics of neural invasion, surgical resection for pancreatic carcinoma is difficult. In addition, pancreatic ductal adenocarcinoma cancer is not sensitive to radiotherapy and chemotherapy. Therefore, the prognosis of pancreatic cancer patients is poor. The incidence of pancreatic cancer and mortality is still increasing in the world. In order to improve the diagnosis and prognosis of pancreatic cancer, there is an urgent need to develop molecular targets for early diagnosis and effective treatment of pancreatic cancer. With the development of biological technology, methods of expression high-throughput detection of gene microarray technology constantly updated.DNA and two generation sequencing gene provides simple and effective methods in order to study the differences of pancreatic cancer tissues and normal tissues. Objective: To investigate the expression of Cable molecular mechanism and progression of pancreatic cancer, this study using microarray data in the GEO database of gene expression differences between mining pancreatic cancer and normal pancreatic tissues, and provide a theoretical basis for clinical treatment of early diagnosis of pancreatic cancer. Methods: pancreatic cancer gene downloaded from the GEO database of gene expression microarray data. Analysis of differential expression of pancreatic cancer tissues and adjacent tissues. The differential expression of standard fold difference is greater than 2 and the P value is less than 0.05. the differentially expressed genes were significant signal pathway enrichment, and to build the topological structure of signaling network graph, find the core signaling pathways in the network topology, and the gene in patients with pancreatic cancer survival analysis of differential expression of this pathway. Results: We obtained expression data of 32 common significant signal pathway and 13 in the six group of pancreatic cancer GEO A common core signaling pathway. Cancer signal pathway is the most important of the 13 core signaling pathways. Cancer signaling pathway in the six groups of the database contains 137 differentially expressed genes, including BIRC5, C/KS2, ITGA3, ITGA6 and RAL genes also showed high expression of survival time of patients with pancreatic cancer in low gene the expression of TCGA and ICGC patients in the database. The expression level of CKS2 gene copy number was positively correlated with the degree of methylation was negatively correlated. Cell experiments showed that decreased expression of CKS2 and BxPC3 can inhibit the proliferation of CFPAC1 cells. Conclusion: by constructing the signal transduction network topology discovery play an important role in the process of cancer pathway occurred in the development of pancreatic cancer, CKS2 gene in this pathway promotes proliferation of pancreatic cancer cells, CKS2 for study of the molecular mechanism in pancreatic cancer to clarify the pancreas The mechanism of carcinogenesis and development plays an important role.

【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R735.9

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