Werle Bernd, Schanzenbächer Ulrike, Lah Tamara Turensek, Ebert Eileen, Jülke Britta, Ebert Werner, Fiehn Werner, Kayser Klaus, Spiess Eberhard, Abrahamson Magnus, Kos Janko
Abteilung für Klinische Chemie und Bakteriologie, Thoraxklinik Heidelberg gGmbH, D-69117 Heidelberg, Germany.
Oncol Rep. 2006 Oct;16(4):647-55.
Cystatins regulate tumour-associated cysteine proteases, however, their role in tumour progression is not clear yet. To assess their relevance in the progression of non-small cell lung cancer (NSCLC) the protein level, cysteine protease activity (CPI) and localization of type I (stefins A and B) and type II (C, E/M and F) cystatins were defined in tumours and control lung counterparts from 165 patients. The medians of CPI activity, stefins A and B were significantly greater in tumour than in lung tissue (2.1-fold, 1.7-fold, 1.2-fold, respectively, all p<0.001). The median levels of cystatin C and cystatin E/M were lower in tumour tissue (0.9-fold, p=0.06; 0.6-fold, p<0.01). In all the samples the levels of cystatin F were below the detection limit. Immunohistochemical analysis revealed the presence of all cystatins in tumour cells and infiltrated inflammatory cells such as macrophages and neutrophils. In univariate survival analysis patients with high levels of stefin A, stefin B and CPI activity exhibited a better survival probability (p=0.05, p=0.05, p<0.01, respectively). In contrast, cystatins C and E/M provided no prognostic information. In multivariate analysis the most powerful predictor of survival was the pTNM stage (p<0.0001; RR 3.5), followed by stefin A, stefin B and CPI activity (all p=0.03; RR 1.5). Our results suggest that only stefins A and B, i.e. type I cystatins, are up-regulated in lung tumours and thus able to counteract harmful tumour-associated proteolytic activity. As biological markers they may add independent prognostic information for better assessment of low- and high-risk patients with NSCLC.
胱抑素可调节肿瘤相关的半胱氨酸蛋白酶，然而，它们在肿瘤进展中的作用尚不清楚。为了评估它们在非小细胞肺癌（NSCLC）进展中的相关性，对165例患者的肿瘤组织和对照肺组织中I型（丝抑素A和B）和II型（胱抑素C、E/M和F）胱抑素的蛋白水平、半胱氨酸蛋白酶活性（CPI）及定位进行了测定。肿瘤组织中CPI活性、丝抑素A和B的中位数显著高于肺组织（分别为2.1倍、1.7倍、1.2倍，均p<0.001）。肿瘤组织中胱抑素C和胱抑素E/M的中位数水平较低（分别为0.9倍，p=0.06；0.6倍，p<0.01）。在所有样本中，胱抑素F的水平低于检测限。免疫组织化学分析显示，肿瘤细胞以及浸润的炎性细胞如巨噬细胞和中性粒细胞中均存在所有的胱抑素。单因素生存分析显示，丝抑素A、丝抑素B和CPI活性水平高的患者生存概率更高（分别为p=0.05、p=0.05、p<0.01）。相比之下，胱抑素C和E/M未提供预后信息。多因素分析中，最强的生存预测指标是pTNM分期（p<0.0001；风险比3.5），其次是丝抑素A、丝抑素B和CPI活性（均p=0.03；风险比1.5）。我们的结果表明，只有丝抑素A和B，即I型胱抑素，在肺肿瘤中上调，因此能够抵消有害的肿瘤相关蛋白水解活性。作为生物标志物，它们可能为更好地评估NSCLC低风险和高风险患者提供独立的预后信息。
