Müller-Tidow C, Metzger R, Kügler K, Diederichs S, Idos G, Thomas M, Dockhorn-Dworniczak B, Schneider P M, Koeffler H P, Berdel W E, Serve H
Department of Medicine, Hematology and Oncology, University of Münster, Germany.
Cancer Res. 2001 Jan 15;61(2):647-53.
Progression through G1-S transition and S phase of the cell cycle is mediated by cyclin-dependent kinase 2 (cdk2), which interacts with several cyclins. Two of these, cyclin E and cyclin A2 (also known as cyclin A), are overexpressed in many cancers. Cyclin E2 and cyclin A1 are recently discovered cdk2-interacting cyclins that are found in malignant tumor cell lines and in acute myeloid leukemia, respectively. Expression and prognostic role of these cyclins in solid tumors is unknown. Here, we have analyzed expression and prognostic relevance of the cdk2-associated cyclins in non-small cell lung cancer (NSCLC). Fresh-frozen biopsies (n = 70) from completely resected tumors with stage I to IIIA NSCLC were studied. Gene expression was analyzed by quantitative real-time reverse transcription-PCR. Expression levels of cyclin E (P = 0.04) and cyclin A2 (P = 0.004) were significantly higher in the tumor samples than in normal controls. Cyclin A1, cyclin A2, and cyclin E2 expression levels did not have prognostic relevance for survival. The mean survival time associated with low and high levels of cyclin E was 69.4 and 47.2 months, respectively, which was statistically significant (P = 0.03). Differences in survival were particularly pronounced in stages I and II. Cyclin E was also closely associated with the development of distant metastasis (P = 0.01). Finally, we confirmed by immunohistochemistry analyses that cyclin E mRNA expression was closely associated with cyclin E protein expression. In conclusion, cyclin E is a strong independent prognostic indicator in patients with early-stage NSCLC, whereas cyclin E2, cyclin A1, and cyclin A2 do not have a prognostic role in NSCLC.
细胞周期从G1期向S期的过渡以及S期的进程由细胞周期蛋白依赖性激酶2（cdk2）介导，cdk2可与多种细胞周期蛋白相互作用。其中两种，即细胞周期蛋白E和细胞周期蛋白A2（也称为细胞周期蛋白A），在许多癌症中均有过表达。细胞周期蛋白E2和细胞周期蛋白A1是最近发现的与cdk2相互作用的细胞周期蛋白，分别存在于恶性肿瘤细胞系和急性髓系白血病中。这些细胞周期蛋白在实体瘤中的表达及预后作用尚不清楚。在此，我们分析了与cdk2相关的细胞周期蛋白在非小细胞肺癌（NSCLC）中的表达及预后相关性。研究了70例I期至IIIA期NSCLC完全切除肿瘤的新鲜冷冻活检组织。通过定量实时逆转录PCR分析基因表达。肿瘤样本中细胞周期蛋白E（P = 0.04）和细胞周期蛋白A2（P = 0.004）的表达水平显著高于正常对照。细胞周期蛋白A1、细胞周期蛋白A2和细胞周期蛋白E2的表达水平与生存无预后相关性。细胞周期蛋白E低水平和高水平相关的平均生存时间分别为69.4个月和47.2个月，具有统计学意义（P = 0.03）。生存差异在I期和II期尤为明显。细胞周期蛋白E也与远处转移的发生密切相关（P = 0.01）。最后，我们通过免疫组织化学分析证实细胞周期蛋白E mRNA表达与细胞周期蛋白E蛋白表达密切相关。总之，细胞周期蛋白E是早期NSCLC患者强有力的独立预后指标，而细胞周期蛋白E2、细胞周期蛋白A1和细胞周期蛋白A2在NSCLC中无预后作用。
