Diederichs Sven, Bulk Etmar, Steffen Björn, Ji Ping, Tickenbrock Lara, Lang Kerstin, Zänker Kurt S, Metzger Ralf, Schneider Paul M, Gerke Volker, Thomas Michael, Berdel Wolfgang E, Serve Hubert, Müller-Tidow Carsten
Department of Medicine, Hematology/Oncology, University of Münster, Münster, Germany.
Cancer Res. 2004 Aug 15;64(16):5564-9. doi: 10.1158/0008-5472.CAN-04-2004.
Distant metastasis is the predominant cause of death in early-stage non-small cell lung cancer (NSCLC). Currently, it is impossible to predict the occurrence of metastasis at early stages and thereby separate patients who could be cured by surgical resection alone from patients who would benefit from additional chemotherapy. In this study, we applied a comparative microarray approach to identify gene expression differences between early-stage NSCLC patients whose cancer ultimately did or did not metastasize during the course of their disease. Transcriptional profiling of 82 microarrays from two patient groups revealed differential expression of several gene families including known predictors of metastasis (e.g., matrix metalloproteinases). In addition, we found S100P, S100A2, trypsinogen C (TRY6), and trypsinogen IVb (PRSS3) to be overexpressed in tumors that metastasized during the course of the disease. In a third group of 42 patients, we confirmed the induction of S100 proteins and trypsinogens in metastasizing tumors and its significant correlation with survival by real-time quantitative reverse transcription-PCR. Overexpression of S100A2, S100P, or PRSS3 in NSCLC cell cultures led to increased transendothelial migration, corroborating the role of S100A2, S100P, and PRSS3 in the metastatic process. Taken together, we provide evidence that expression of S100 proteins and trypsinogens is associated with metastasis and predicts survival in early stages of NSCLC. For the first time, this implicates a role of S100 proteins and trypsinogens in the metastatic process of early-stage NSCLC.
远处转移是早期非小细胞肺癌（NSCLC）患者死亡的主要原因。目前，尚无法在疾病早期预测转移的发生，从而将仅通过手术切除即可治愈的患者与可从辅助化疗中获益的患者区分开来。在本研究中，我们采用比较性微阵列方法来鉴定疾病过程中最终发生或未发生转移的早期NSCLC患者之间的基因表达差异。对来自两个患者组的82个微阵列进行转录谱分析，结果显示包括已知转移预测因子（如基质金属蛋白酶）在内的几个基因家族存在差异表达。此外，我们发现S100P、S100A2、胰蛋白酶原C（TRY6）和胰蛋白酶原IVb（PRSS3）在疾病过程中发生转移的肿瘤中过表达。在第三组42例患者中，我们通过实时定量逆转录PCR证实了转移瘤中S100蛋白和胰蛋白酶原的诱导表达及其与生存的显著相关性。NSCLC细胞培养物中S100A2、S100P或PRSS3的过表达导致跨内皮迁移增加，这证实了S100A2、S100P和PRSS3在转移过程中的作用。综上所述，我们提供的证据表明，S100蛋白和胰蛋白酶原的表达与转移相关，并可预测早期NSCLC患者的生存情况。首次证明S100蛋白和胰蛋白酶原在早期NSCLC转移过程中发挥作用。
