Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden SE-141 86;
Mol Cell Proteomics. 2014 Mar;13(3):701-15. doi: 10.1074/mcp.M113.030775. Epub 2013 Dec 20.
Malignant mesothelioma is an aggressive asbestos-induced cancer, and affected patients have a median survival of approximately one year after diagnosis. It is often difficult to reach a conclusive diagnosis, and ancillary measurements of soluble biomarkers could increase diagnostic accuracy. Unfortunately, few soluble mesothelioma biomarkers are suitable for clinical application. Here we screened the effusion proteomes of mesothelioma and lung adenocarcinoma patients to identify novel soluble mesothelioma biomarkers. We performed quantitative mass-spectrometry-based proteomics using isobaric tags for quantification and used narrow-range immobilized pH gradient/high-resolution isoelectric focusing (pH 4-4.25) prior to analysis by means of nano liquid chromatography coupled to MS/MS. More than 1,300 proteins were identified in pleural effusions from patients with malignant mesothelioma (n = 6), lung adenocarcinoma (n = 6), or benign mesotheliosis (n = 7). Data are available via ProteomeXchange with identifier PXD000531. The identified proteins included a set of known mesothelioma markers and proteins that regulate hallmarks of cancer such as invasion, angiogenesis, and immune evasion, plus several new candidate proteins. Seven candidates (aldo-keto reductase 1B10, apolipoprotein C-I, galectin 1, myosin-VIIb, superoxide dismutase 2, tenascin C, and thrombospondin 1) were validated by enzyme-linked immunosorbent assays in a larger group of patients with mesothelioma (n = 37) or metastatic carcinomas (n = 25) and in effusions from patients with benign, reactive conditions (n = 16). Galectin 1 was identified as overexpressed in effusions from lung adenocarcinoma relative to mesothelioma and was validated as an excellent predictor for metastatic carcinomas against malignant mesothelioma. Galectin 1, aldo-keto reductase 1B10, and apolipoprotein C-I were all identified as potential prognostic biomarkers for malignant mesothelioma. This analysis of the effusion proteome furthers our understanding of malignant mesothelioma, identified galectin 1 as a potential diagnostic biomarker, and highlighted several possible prognostic biomarkers of this disease.
恶性间皮瘤是一种由石棉引起的侵袭性癌症，确诊后患者的中位生存期约为一年。恶性间皮瘤的诊断通常较为困难，而辅助可溶性生物标志物的测量可能会提高诊断的准确性。然而，适合临床应用的可溶性间皮瘤生物标志物却很少。在此，我们通过筛选间皮瘤和肺腺癌患者的胸水中的蛋白质组，来鉴定新的可溶性间皮瘤生物标志物。我们使用等重同位素标记相对和绝对定量技术（isobaric tags for quantification）进行定量质谱蛋白质组学分析，并用窄范围固定 pH 值梯度/高分辨率等电聚焦（pH 4-4.25）进行分析，随后通过纳升液相色谱与 MS/MS 联用。在 6 例恶性间皮瘤、6 例肺腺癌和 7 例良性间皮瘤患者的胸腔积液中鉴定出 1300 多种蛋白质。数据已通过 ProteomeXchange 以标识符 PXD000531 发布。所鉴定的蛋白质包括一组已知的间皮瘤标志物和调节癌症特征的蛋白质，如侵袭、血管生成和免疫逃逸，以及一些新的候选蛋白。通过酶联免疫吸附试验（enzyme-linked immunosorbent assays），在更大的一组间皮瘤（n = 37）或转移性癌（n = 25）患者和良性、反应性疾病患者的胸腔积液（n = 16）中验证了 7 个候选蛋白（醛酮还原酶 1B10、载脂蛋白 C-I、半乳糖凝集素 1、肌球蛋白-VIIb、超氧化物歧化酶 2、腱糖蛋白 C 和血栓反应蛋白 1）。与间皮瘤相比，半乳糖凝集素 1在肺腺癌患者的胸腔积液中表达上调，并被验证为转移性癌与恶性间皮瘤的优秀预测因子。半乳糖凝集素 1、醛酮还原酶 1B10 和载脂蛋白 C-I 均被鉴定为恶性间皮瘤的潜在预后生物标志物。本研究通过对胸腔积液蛋白质组的分析，进一步了解了恶性间皮瘤，鉴定出半乳糖凝集素 1 作为潜在的诊断生物标志物，并强调了该疾病的几个可能的预后生物标志物。
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