Singhal Sunil, Wiewrodt Rainer, Malden Liliana D, Amin Kunjlata M, Matzie Kimberly, Friedberg Joseph, Kucharczuk John C, Litzky Leslie A, Johnson Steven W, Kaiser Larry R, Albelda Steven M
Section of Thoracic Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Clin Cancer Res. 2003 Aug 1;9(8):3080-97.
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.
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.
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.
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.
恶性间皮瘤是一种发生于胸膜和腹膜腔的、预后一致较差的癌症。它存在几个具有挑战性的临床问题，包括对病理生理学了解不足、从组织样本中进行不准确的诊断以及不成功的治疗策略。本研究的目的是利用微阵列分析来确定间皮瘤与正常间皮相比特定的基因表达变化。
我们对16例患者的间皮瘤组织标本进行了基因表达分析，并使用含有4132个克隆的cDNA微阵列滤膜将这些标本与4个对照胸膜组织样本进行比较。采用了多种标准化和分析方法。使用定量逆转录 - 聚合酶链反应和免疫组织化学来验证结果。
166个基因显著上调，26个基因下调。使用实时聚合酶链反应对18个基因进行验证，在每种情况下均证实了微阵列预测结果。分析显示包括参与葡萄糖代谢、mRNA翻译和细胞骨架重塑的基因在内的几个关键途径被激活。表达谱分析确定了可能导致正电子发射断层扫描中18 - 氟 - 2 - 脱氧 - 葡萄糖摄取和肿瘤定位的过程，并提示了缺氧诱导因子 - 1的作用。潜在重要的上调基因包括gp96、肺抗性相关蛋白、半乳糖凝集素 - 3结合蛋白、67000分子量的层粘连蛋白受体（在肿瘤血管上）和电压依赖性阴离子通道。使用逆转录 - 聚合酶链反应进行的前瞻性检测证实了这些新标志物的上调。
表达谱分析显示间皮瘤中能量、蛋白质翻译和细胞骨架重塑途径显著上调。还鉴定出了一些在我们理解间皮瘤发病机制、辅助诊断或改善治疗靶点方面可能重要的其他基因。
