EphrinA1在神经胶质瘤中的作用及食管癌的蛋白质组学研究
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摘要
论文中对EphrinA1在神经胶质瘤中的功能作了一定的研究,同时也对食管鳞癌进行了蛋白质组分析。
Eph受体是最大的受体酪氨酸激酶家族,与它们的配体Ephrin在神经系统发育过程中神经元的轴突导向、细胞迁移都有重要作用。最近发现这些分子与一些肿瘤的发生有关。在我们的研究中,发现在神经胶质瘤细胞株中几乎检测不到EphrinA1的表达,同时,与相邻的正常组织相比,原发的神经胶质瘤中EphrinA1的表达量明显下降。在U251细胞中过表达EphrinA1会降低细胞生长、迁移以及非依赖性生长能力;过表达EphrinA1还会促进其受体EphA2的磷酸化水平升高,从而导致后者的蛋白降解;另外,EphA2的一个已知下游分子FAK,在这些过表达EphrinA1的细胞中也有下调。这些结果表明EphrinA1在神经胶质瘤发生过程中,可能通过下调EphA2以及FAK来负调控肿瘤的发生,因此,可以作为一个肿瘤治疗的潜在靶基因。
食管鳞癌是中国主要的食管癌亚型,有高发病率及高死亡率的特点,其临床诊断主要是依据食管组织学的变化来确定的,但是,大多数低级别的病人并没有表现出明显的组织学变化,因此,更深入了解肿瘤进程的机制以及找到一些级别特异的分子对我们诊断、治疗食管鳞癌提供帮助。在这个研究当中,我们应用蛋白质组学方法对不同级别(TNM分级法)的食管鳞癌组织进行分析,测定与食管鳞癌进程(从第一级到第三级)相关的蛋白质组特征,将在食管鳞癌与相应正常组织中表达差异非常明显的蛋白点用质谱方法进行鉴定,鉴定出来的差异蛋白主要归为三类(骨架系统相关的蛋白、代谢相关的酶类、热激蛋白)。另外,通过实时定量PCR,我们发现enolase 1,chromosome 1 open reading frame 10,elastase inhibitor,alpha B crystalline,stress induced phosphoprotein 1以及squamous cell carcinoma antigen 1六个基因在mRNA水平上与肿瘤级别有一定的相关性。总之,我们的数据为食管鳞癌的进程提供了更加丰富的信息,并且为食管鳞癌的临床治疗提供了潜在的药物靶分子。
THE FUNCTION OF EPHRINA1 IN GLIOMA
Eph receptors, the largest receptor tyrosine kinases, and their ephrin ligands play important roles in axon guidance and cell migration during development of the nervous system. Recently, these molecules are also found involved in tumorigenesis of different kinds of cancers. In this study, we demonstrated that expression of ephrin-A1 was dramatically down-regulated in glioma cell lines as well as in primary gliomas comparing to the matched normal tissues. Forced expression of ephrin-A1 attenuated cell migration, cell proliferation, and adhesion-independent growth in human glioma U251 cells. Overexpression of ephrin-A1 stimulated activation of EphA2, a receptor for ephrin-A1 and an oncoprotein, by phosphorylation and leaded the latter to degradation. Furthermore, focal adhesion kinase (FAK), a known downstream molecule of EphA2, was also down-regulated in those ephrin-A1 transfected cells. These results suggested that ephrin-A1 served as a critical negative regulator in the tumorigenesis of gliomas by down-regulating EphA2 and FAK, which may provide potential valuable targets for therapeutic intervention.
PROTEOMIC ANALYSIS OF ESOPHAGEAL SQUAMOUS CELL CARCINOMA
Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancers in China, and characterized with high morbidity and mortality. So far, the diagnosis of ESCC is mainly dependent on the alterations in esophageal histology, but most cases of ESCC with low stage do not display visible histological abnormalities. Therefore deep understanding the mechanism of ESCC progression and seeking stage-specific molecules might improve the diagnosis and therapy for ESCC. In this study, we used proteomics to analyze ESCC tissues with classification by TNM stage, and determined the proteomic features correlated with ESCC progression (from stage I to III). Proteins that exhibited significantly differential expressions between ESCC and corresponding normal esophageal tissues were identified by using mass spectrometry. The identified proteins with differentiated expression mainly fell into three protein categories (i.e. cytoskeleton system associated proteins, metabolism enzymes, and heat shock proteins). In addition, real-time PCR displayed that some molecules were associated with tumor stages in mRNA level, such as enolase 1, chromosome 1 open reading frame 10, elastase inhibitor, alpha B crystalline, stress induced phosphoprotein 1, and squamous cell carcinoma antigen 1. Altogether, these data provided further information on ESCC progression and potential drug targets for ESCC clinical therapy.
Eph受体是最大的受体酪氨酸激酶家族,与它们的配体Ephrin在神经系统发育过程中神经元的轴突导向、细胞迁移都有重要作用。最近发现这些分子与一些肿瘤的发生有关。在我们的研究中,发现在神经胶质瘤细胞株中几乎检测不到EphrinA1的表达,同时,与相邻的正常组织相比,原发的神经胶质瘤中EphrinA1的表达量明显下降。在U251细胞中过表达EphrinA1会降低细胞生长、迁移以及非依赖性生长能力;过表达EphrinA1还会促进其受体EphA2的磷酸化水平升高,从而导致后者的蛋白降解;另外,EphA2的一个已知下游分子FAK,在这些过表达EphrinA1的细胞中也有下调。这些结果表明EphrinA1在神经胶质瘤发生过程中,可能通过下调EphA2以及FAK来负调控肿瘤的发生,因此,可以作为一个肿瘤治疗的潜在靶基因。
食管鳞癌是中国主要的食管癌亚型,有高发病率及高死亡率的特点,其临床诊断主要是依据食管组织学的变化来确定的,但是,大多数低级别的病人并没有表现出明显的组织学变化,因此,更深入了解肿瘤进程的机制以及找到一些级别特异的分子对我们诊断、治疗食管鳞癌提供帮助。在这个研究当中,我们应用蛋白质组学方法对不同级别(TNM分级法)的食管鳞癌组织进行分析,测定与食管鳞癌进程(从第一级到第三级)相关的蛋白质组特征,将在食管鳞癌与相应正常组织中表达差异非常明显的蛋白点用质谱方法进行鉴定,鉴定出来的差异蛋白主要归为三类(骨架系统相关的蛋白、代谢相关的酶类、热激蛋白)。另外,通过实时定量PCR,我们发现enolase 1,chromosome 1 open reading frame 10,elastase inhibitor,alpha B crystalline,stress induced phosphoprotein 1以及squamous cell carcinoma antigen 1六个基因在mRNA水平上与肿瘤级别有一定的相关性。总之,我们的数据为食管鳞癌的进程提供了更加丰富的信息,并且为食管鳞癌的临床治疗提供了潜在的药物靶分子。
THE FUNCTION OF EPHRINA1 IN GLIOMA
Eph receptors, the largest receptor tyrosine kinases, and their ephrin ligands play important roles in axon guidance and cell migration during development of the nervous system. Recently, these molecules are also found involved in tumorigenesis of different kinds of cancers. In this study, we demonstrated that expression of ephrin-A1 was dramatically down-regulated in glioma cell lines as well as in primary gliomas comparing to the matched normal tissues. Forced expression of ephrin-A1 attenuated cell migration, cell proliferation, and adhesion-independent growth in human glioma U251 cells. Overexpression of ephrin-A1 stimulated activation of EphA2, a receptor for ephrin-A1 and an oncoprotein, by phosphorylation and leaded the latter to degradation. Furthermore, focal adhesion kinase (FAK), a known downstream molecule of EphA2, was also down-regulated in those ephrin-A1 transfected cells. These results suggested that ephrin-A1 served as a critical negative regulator in the tumorigenesis of gliomas by down-regulating EphA2 and FAK, which may provide potential valuable targets for therapeutic intervention.
PROTEOMIC ANALYSIS OF ESOPHAGEAL SQUAMOUS CELL CARCINOMA
Esophageal squamous cell carcinoma (ESCC) is the major subtype of esophageal cancers in China, and characterized with high morbidity and mortality. So far, the diagnosis of ESCC is mainly dependent on the alterations in esophageal histology, but most cases of ESCC with low stage do not display visible histological abnormalities. Therefore deep understanding the mechanism of ESCC progression and seeking stage-specific molecules might improve the diagnosis and therapy for ESCC. In this study, we used proteomics to analyze ESCC tissues with classification by TNM stage, and determined the proteomic features correlated with ESCC progression (from stage I to III). Proteins that exhibited significantly differential expressions between ESCC and corresponding normal esophageal tissues were identified by using mass spectrometry. The identified proteins with differentiated expression mainly fell into three protein categories (i.e. cytoskeleton system associated proteins, metabolism enzymes, and heat shock proteins). In addition, real-time PCR displayed that some molecules were associated with tumor stages in mRNA level, such as enolase 1, chromosome 1 open reading frame 10, elastase inhibitor, alpha B crystalline, stress induced phosphoprotein 1, and squamous cell carcinoma antigen 1. Altogether, these data provided further information on ESCC progression and potential drug targets for ESCC clinical therapy.
引文
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