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Identification of the Transmembrane Glucose Regulated Protein 78 as a Biomarker for the Brain Cancer Glioblastoma Multiforme by Gene Expression and Proteomic Studies. 通过基因表达和蛋白质组学研究鉴定跨膜葡萄糖调节蛋白78作为多形性脑癌胶质母细胞瘤的生物标志物。
Pub Date : 2014-02-15 DOI: 10.4172/2155-9589.1000126
H N Banerjee, G Hyman, S Evans, V Manglik, E Gwebu, A Banerjee, D Vaughan, J Medley, C Krauss, J Wilkins, V Smith, A Banerji, J Rousch

The prognosis of patients with Glioblastoma Multiforme (GBM), the most malignant adult glial brain tumor, remains poor in spite of advances in treatment procedures, including surgical resection, irradiation and chemotherapy. Genetic heterogeneity of GBM warrants extensive studies to gain a thorough understanding of the biology of this tumor. While there have been several studies of global transcript profiling of glioma with the identification of gene signatures for diagnosis and disease management, translation into clinics is yet to happen. In the present study, we report a novel proteomic approach by using two-dimensional difference gel electrophoresis (2D-DIGE) followed by spot picking and analysis of proteins/peptides by Mass Spectrometry. We report Glucose Regulated Protein 78 (GRP78) as a differentially expressed protein in the GBM cell line compared to human normal Astrocyte cells. In addition to proteomic studies, we performed microarray analysis which further confirmed up regulation of GRP78 in GBM cells compared to human normal Astrocyte cells. GRP78 has long been recognized as a molecular chaperone in the endoplasmic reticulum (ER) and can be induced by the ER stress response. Besides its location in the ER, GRP78 has been found in cell plasma membrane, cytoplasm, mitochondria, nucleus and other cellular secretions. GRP78 is implicated in tumor cell proliferation, apoptosis resistance, immune escape, metastasis and angiogenesis, and its elevated expression usually correlates with a variety of tumor micro environmental stresses, including hypoxia, glucose deprivation, lactic acidosis and inflammatory response. GRP78 protein acts as a centrally located sensor of stress, which senses and facilitates the adaptation to the tumor microenvironment. Our findings showed differential expression of this gene in brain cancer GBM and thus confirm similarities in findings in existing transcriptional and translational studies. Thus, these findings could be of further importance for diagnostic, therapeutic and prognostic approaches for dealing with this highly malignant cancer.

多形性胶质母细胞瘤(GBM)是最恶性的成人胶质性脑肿瘤,尽管治疗方法取得了进展,包括手术切除、放疗和化疗,但其预后仍然很差。GBM的遗传异质性值得广泛的研究,以获得对该肿瘤生物学的透彻理解。虽然已经有一些关于神经胶质瘤的全球转录谱分析的研究,并确定了用于诊断和疾病管理的基因特征,但转化为临床尚未发生。在本研究中,我们报告了一种新的蛋白质组学方法,即使用二维差异凝胶电泳(2D-DIGE),然后用质谱法对蛋白质/肽进行斑点挑选和分析。我们报道葡萄糖调节蛋白78 (GRP78)在GBM细胞系中与人类正常星形胶质细胞相比存在差异表达。除了蛋白质组学研究外,我们还进行了微阵列分析,进一步证实了与人类正常星形胶质细胞相比,GBM细胞中GRP78的上调。GRP78一直被认为是内质网(ER)中的分子伴侣,并可由内质网应激反应诱导。GRP78除位于内质网外,还存在于细胞膜、细胞质、线粒体、细胞核等细胞分泌物中。GRP78参与肿瘤细胞增殖、凋亡抵抗、免疫逃逸、转移和血管生成,其表达升高通常与多种肿瘤微环境应激相关,包括缺氧、葡萄糖剥夺、乳酸酸中毒和炎症反应。GRP78蛋白作为应激的中心传感器,感知并促进对肿瘤微环境的适应。我们的研究结果显示该基因在脑癌GBM中的差异表达,从而证实了现有转录和转化研究结果的相似性。因此,这些发现可能对治疗这种高度恶性癌症的诊断、治疗和预后方法具有进一步的重要性。
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Journal of membrane science & technology
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