人肝癌发生的蛋白质组学研究及ANXA4等蛋白质的表达与功能验证
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摘要
人类肝癌是诊治困难、预后极差的一种恶性肿瘤，其发生发展是多因素参与的多环节的病理过程，传统的单基因研究模式限制了肝癌相关因素的研究发展。近年来迅速发展的蛋白质组学研究，能动态、整体、定量地考察疾病发生发展过程中全部蛋白质种类和数量的变化，对于探讨疾病发病机理、寻找疾病诊断的特异性标志物和药物治疗的靶标来说，是一种有效的高通量的研究模式，可获得一些传统手段无法得到的新蛋白标志物、新关键分子，极大地丰富了诊断标志物的选择组合及复杂致病机理的全面阐明。本研究运用蛋白质组学研究方法及手段，通过对人类正常肝组织、乙型肝炎组织、肝硬化肝组织、肝细胞性肝癌组织的全蛋白质组表达谱差异分析，筛选出了一些有潜在应用价值的差异蛋白质，对其中的差异分子annexins A4(ANXA4)、PeroxiredoxinⅡ(PrxⅡ)、PeroxiredoxinⅢ(PrxⅢ)在肝癌组织中进行表达验证，并采用RNA干扰技术以及癌发生相关生物学特性的鉴定方法对ANXA4进行了功能分析。
第一部分 人肝细胞性肝癌发生相关的蛋白质组学研究
本部分应用双向凝胶电泳(two-dimensional electrophoresis，2-DE)结合基质辅助的激光解析离子化-飞行时间质谱(matrix assisted laser desorption／ionization-time of flight mass spectrometry，MALDI-TOF-MS)等蛋白质组学技术，对正常肝组织、乙型肝炎组织、肝硬化肝组织、肝细胞性肝癌组织的全蛋白质差异表达谱进行分析，筛查在肝癌发生过程中发挥重要作用的差异蛋白分子。
选择正常人肝组织(A组)5例，以及临床病理确定为乙型肝炎的肝组
Hepatocellular carcinoma (HCC), of which the morbidity and mortality are in the forefront among the overall tumors worldwide, is one of the malignancies with difficult in early diagnosis and extremely poor prognosis. The formation of HCC is a multistep, multistage and multifactor process like most other tumors. The conventional strategy of research on single gene has been challenged by the rapidly progress of proteomics, which can be utilized to observe the dynamical changes of nature and quantity of total protein during progression of disease. Proteomics can be used to find new protein markers and key molecules and therefore is an effective and high-throughout method for exploring mechanism of disease and for searching targets of diagnosis or therapy. By optimizing the technical platform of two-dimensional electrophoresis (2-DE), in the present study we observed dynamically the differentially expressed proteins of liver tissue during carcinogenesis and progression of human Hepatocellular Carcinoma,which including normal liver tissue, chronic type B hepatitis tissue, cirrhotic tissues, HCC tissue.We got a group of significant differential proteins, and ANXA4、 PrxⅡ、PrxⅢproteins which may be related to hepatocarcinogenesis was further confirmed by Western blot and RT-PCR. We also drew a positive conclusion through further analysis and validation of the biological function of ANXA4 with RNA interference technique and some following experiments related to cell properties of carcinogenesis. The entire study included four parts as following.
第一部分 人肝细胞性肝癌发生相关的蛋白质组学研究
本部分应用双向凝胶电泳(two-dimensional electrophoresis，2-DE)结合基质辅助的激光解析离子化-飞行时间质谱(matrix assisted laser desorption／ionization-time of flight mass spectrometry，MALDI-TOF-MS)等蛋白质组学技术，对正常肝组织、乙型肝炎组织、肝硬化肝组织、肝细胞性肝癌组织的全蛋白质差异表达谱进行分析，筛查在肝癌发生过程中发挥重要作用的差异蛋白分子。
选择正常人肝组织(A组)5例，以及临床病理确定为乙型肝炎的肝组
Hepatocellular carcinoma (HCC), of which the morbidity and mortality are in the forefront among the overall tumors worldwide, is one of the malignancies with difficult in early diagnosis and extremely poor prognosis. The formation of HCC is a multistep, multistage and multifactor process like most other tumors. The conventional strategy of research on single gene has been challenged by the rapidly progress of proteomics, which can be utilized to observe the dynamical changes of nature and quantity of total protein during progression of disease. Proteomics can be used to find new protein markers and key molecules and therefore is an effective and high-throughout method for exploring mechanism of disease and for searching targets of diagnosis or therapy. By optimizing the technical platform of two-dimensional electrophoresis (2-DE), in the present study we observed dynamically the differentially expressed proteins of liver tissue during carcinogenesis and progression of human Hepatocellular Carcinoma,which including normal liver tissue, chronic type B hepatitis tissue, cirrhotic tissues, HCC tissue.We got a group of significant differential proteins, and ANXA4、 PrxⅡ、PrxⅢproteins which may be related to hepatocarcinogenesis was further confirmed by Western blot and RT-PCR. We also drew a positive conclusion through further analysis and validation of the biological function of ANXA4 with RNA interference technique and some following experiments related to cell properties of carcinogenesis. The entire study included four parts as following.
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