应用生物信息学方法对HPV相关口咽癌的分子生物学研究

发布时间：2018-01-29 06:27

本文关键词： HPV 口咽癌生物信息学蛋白质交互作用网络聚类分析　出处：《浙江大学》2015年博士论文　论文类型：学位论文

【摘要】：研究背景：口咽癌(Oropharyngeal Squamous Cell Carcinoma, OPSCC)是头颈部常见的恶性肿瘤。近年来,人乳头状瘤病毒(Human Papilloma Virus, HPV)感染,被认为是除吸烟和饮酒外另一个重要的致病因素。临床研究发现感染HPV与未感染HPV的OPSCC患者的临床特征和预后不同。国际癌症研究机构的研究表明HPV感染的OPSCC患者可进一步细分为HPV激活组和HPV未激活组,前者明显较后者及HPV阴性口咽癌患者预后好。HPV在口咽癌的致病机理仍未被阐明。研究目的：分析HPV激活、HPV未激活和HPV阴性三种OPSCC的基因芯片数据。结合基因芯片数据和蛋白质数据库,构建并分析三种OPSCC蛋白质-蛋白质相互作用(Protein-Protein Interaction, PPI)网络。研究方法： 1、使用R程序的Limma数据包将HPV激活、HPV未激活和HPV阴性三种OPSCC与正常口咽组织的基因芯片数据分别进行比较,获取三组的差异性表达基因(Differentially Expressed Genes, DEGs),并进行GO (Gene Ontology)分析和KEGG通路分析。 2、合并HPRD、 MINT、 BioGRID三大蛋白质数据库中的蛋白质交互作用(Protein-Protein Interaction, PPI)数据,制作PPI数据库。 3、根据三组DEGs信息,结合PPI数据库信息,构造三种OPSCC相对应的蛋白质交互作用网络,使用ClusterOne进行聚类分析。研究结果： 1、与正常口咽组织的基因芯片相比,HPV激活组有184个基因,HPV未激活组有482个基因,HPV阴性组有543个基因存在显著的差异性表达。三组DEGs的功能分析提示这些DEGs均集中在“上皮发育”、“上皮分化”、“细胞黏附”、“生物黏附”、“胞外基质”、“细胞因子活性”等条目上。 2、三种OPSCC相对应的PPI网络被建立。对其进行聚类分析后发现,COL1A1是三张网络共同的热点蛋白,UBC及CEACAMs是HPV未激活和HPV阴性OPSCC的PPI网络的热点蛋白。研究结论： 1、上皮发育分化、细胞黏附、胞外基质改变及细胞因子紊乱在OPSCC发生发展中可能起到重要作用。 2、同HPV激活OPSCC相比,HPV未激活与HPV阴性OPSCC有更多相似的分子生物学标记物。 3、COL1A1可能是OPSCC的重要生物标记物,UBC及CEACAMs可能是HPV未激活和HPV阴性OPSCC的重要生物标记物。
[Abstract]:Background: Oropharyngeal Squamous Cell carcinoma (OPSCC) is a common malignant tumor in head and neck. Human Papilloma virus (HPV) infection. It is considered to be another important pathogenic factor in addition to smoking and drinking. Clinical studies have found that the clinical characteristics and prognosis of OPSCC patients infected with HPV are different from those of OPSCC patients without HPV. The results showed that OPSCC patients infected with HPV could be further subdivided into HPV activated group and HPV inactive group. The prognosis of the former was significantly better than that of the latter and the HPV negative oropharyngeal carcinoma. The pathogenesis of HPVin oropharyngeal carcinoma has not been elucidated. Objectives of the study: To analyze the gene chip data of HPV activated HPV-unactivated and HPV negative OPSCC, combined with gene chip data and protein database. Three OPSCC protein-protein interaction networks were constructed and analyzed. Research methods: 1. Using the Limma data of R program, the HPV activated HPV-unactivated and HPV negative OPSCC were compared with the normal oropharyngeal tissue gene chip data. Three groups of differentially expressed Expressed genes (DEGs) were obtained. Go Gene Ontology) analysis and KEGG pathway analysis were carried out. (2) protein interaction in HPRD, mint, BioGRID protein database was combined with Protein-Protein Interaction. PPI) data, the production of PPI database. 3. According to three groups of DEGs information and PPI database information, three kinds of protein interaction networks corresponding to OPSCC are constructed, and cluster analysis is carried out by ClusterOne. Results of the study: 1. Compared with normal oropharyngeal tissue, there were 184 HPV-activated genes in HPV-activated group and 482 genes in non-HPV-activated group. There were significant differences in the expression of 543 genes in the HPV negative group. The functional analysis of DEGs in the three groups suggested that these DEGs were concentrated in "epithelial development", "epithelial differentiation" and "cell adhesion". "Biological adhesion", "extracellular matrix", "cytokine activity", etc. 2, three PPI networks corresponding to OPSCC were established, and the results of cluster analysis showed that COL1A1 was the common hot protein of the three networks. UBC and CEACAMs are hot spots in PPI network of HPV inactive and HPV negative OPSCC. The study concluded that: 1. Epithelial development and differentiation, cell adhesion, extracellular matrix change and cytokine disorder may play an important role in the development of OPSCC. 2. Compared with HPV activated OPSCC, there were more similar molecular biomarkers between unactivated and HPV negative OPSCC. 3COL1A1 may be an important biomarker of OPSCC and CEACAMs may be an important biomarker of HPV unactivated and HPV negative OPSCC.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R739.85

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