Gene expression profiling of malignant mesothelioma.
Gene expression profiling of malignant mesothelioma.
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发表时间：
2003-08
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通讯作者：
S. Singhal;R. Wiewrodt;Liliana D. Malden;K. Amin;Kimberly A. Matzie;J. Friedberg;J. Kucharczuk;L. Litzky;Steven W. Johnson;L. Kaiser;S. Albelda
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作者：
S. Singhal;R. Wiewrodt;Liliana D. Malden;K. Amin;Kimberly A. Matzie;J. Friedberg;J. Kucharczuk;L. Litzky;Steven W. Johnson;L. Kaiser;S. Albelda
恶性间皮瘤是一种发生于胸膜和腹膜腔的致死性肿瘤。几个具有挑战性的临床问题包括对病理生理学的理解不足，组织样本的诊断不准确，以及不成功的治疗策略。本研究的目的是使用微阵列分析，以确定特定的基因表达变化间皮瘤相比，正常间皮瘤。实验设计我们对来自16名患者的间皮瘤组织样本进行基因表达分析，并使用具有4132个克隆的cDNA微阵列过滤器将这些样本与4个对照胸膜组织样本进行比较。使用多种标准化和分析方法。定量逆转录-PCR和免疫组化用于验证结果。结果166个基因表达上调，26个基因表达下调。使用实时PCR验证18个基因证实了每种情况下的阵列预测。分析显示了几个关键途径的激活，包括参与葡萄糖代谢，mRNA翻译和细胞骨架重塑的基因。表达谱确定的过程可能负责18-氟-2-脱氧葡萄糖摄取和肿瘤定位的正电子发射断层扫描，缺氧诱导因子-1的作用被提出。潜在重要的上调基因包括gp 96、肺耐药相关蛋白、半乳糖凝集素-3结合蛋白、M（r）67，000层粘连蛋白受体（在肿瘤血管上）和电压依赖性阴离子通道。使用逆转录-PCR的前瞻性测试证实了这些新标志物的上调。结论：表达谱显示间皮瘤中能量、蛋白质翻译和细胞骨架重塑途径显著上调。其他基因，可能是重要的，在我们的理解间皮瘤的发病机制，帮助诊断，或改善治疗目标也被确定。
PURPOSE Malignant mesothelioma is a uniformly fatal cancer of the pleural and peritoneal spaces. Several challenging clinical problems include poor understanding of the pathophysiology, inaccurate diagnosis from tissue samples, and unsuccessful treatment strategies. The purpose of this study was to use microarray analysis to identify specific gene expression changes in mesothelioma compared with normal mesothelium. EXPERIMENTAL DESIGN We performed gene expression analysis on mesothelioma tissue specimens from 16 patients and compared these to 4 control pleural tissue samples using cDNA microarray filters with 4132 clones. Multiple normalization and analysis approaches were used. Quantitative reverse transcription-PCR and immunohistochemistry were used to validate results. RESULTS Genes (166) were significantly up-regulated, and 26 were down-regulated. Validation of 18 genes using real-time PCR confirmed array predictions in every case. Analysis revealed activation of several key pathways including genes involved in glucose metabolism, mRNA translation, and cytoskeletal remodeling. Expression profiling identified processes likely responsible for 18-fluoro-2-deoxy-glucose uptake and tumor localization by positron emission tomography, and a role for hypoxia-inducible factor-1 was suggested. Potentially important up-regulated genes included gp96, lung resistance-related protein, galectin-3 binding protein, the M(r) 67,000 laminin receptor (on tumor vessels), and voltage-dependent anion channels. Prospective testing using reverse transcription-PCR confirmed up-regulation of these novel markers. CONCLUSIONS Expression profiling revealed marked up-regulation of energy, protein translation, and cytoskeletal remodeling pathways in mesothelioma. Additional genes that could be important in our understanding of the pathogenesis of mesothelioma, aiding in diagnosis, or improving targets for therapy were also identified.