Regulation of p27 by S-phase kinase-associated protein 2 is associated with aggressiveness in non-small-cell lung cancer
Regulation of p27 by S-phase kinase-associated protein 2 is associated with aggressiveness in non-small-cell lung cancer
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DOI：
10.1200/jco.2004.01.035
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发表时间：
2004-10-15
影响因子：
45.3
通讯作者：
Maehara, Y
中科院分区：
文献类型：
--
作者：
Osoegawa, A;Yoshino, I;Maehara, Y
目的F-box蛋白S期激酶相关蛋白2（Skp 2）是细胞周期的正调控因子之一，它促进泛素介导的细胞周期蛋白依赖性激酶抑制剂p27的蛋白水解。本研究旨在探讨Skp 2蛋白在非小细胞肺癌（NSCLC）中的表达及其意义。患者与方法对138例NSCLC患者的临床病理特征和Skp 2、p27蛋白的免疫组化表达进行研究。使用Kaplan-Meier方法和考克斯回归模型进行生存分析。结果Skp 2在男性、吸烟者、鳞状细胞癌患者和低分化癌患者中过表达（P值分别为0.034、<0.0001、<0.0001和0.002）。多因素分析显示Skp 2表达是NSCLC患者生存的独立预后因素。观察到Skp 2与p27表达呈负相关（P = .012），Skp 2表达较高和p27表达较低的患者预后显着不利（P = .0002）。Skp 2在NSCLC细胞中的体外异位表达降低了p27的蛋白水平。结论Skp 2过表达与p27蛋白表达抑制及NSCLC的侵袭性密切相关。它也可能成为NSCLC的治疗靶点。(C)2004年，美国临床肿瘤学会。
Purpose The F-box protein S-phase kinase-associated protein 2 (Skp2) is one of the positive regulators of the cell cycle that promote ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27. In this study, we investigated the significance of Skp2 expression in human non-small-cell lung cancer (NSCLC).Patients and Methods Clinicopathologic features and immunohistochemical expression of Skp2 and p27 proteins were studied in 138 patients with NSCLC. Survival analyses were performed using the Kaplan-Meier method and the Cox regression model. To analyze the role of Skp2 in vitro, NSCLC cells were transfected with an Skp2-expressing vector or small interfering RNA.Results Skp2 was overexpressed in males, smokers, patients with squamous cell carcinomas, and patients with poorly differentiated cancers (P = .034, < .0001, < .0001, and .002, respectively). The multivariant analysis revealed that Skp2 expression is an independent prognostic factor for survival in NSCLC. An inverse relationship of Skp2 with p27 expression was observed (P = .012), and patients with both a higher expression of Skp2 and a lower expression of p27 showed a significantly unfavorable prognosis (P = .0002). In vitro ectopic expression of Skp2 in NSCLC cells reduced the protein level of p27. Conversely, induction of Skp2 siRNA increased the protein level of p27, leading to growth inhibition in NSCLC cells.Conclusion Skp2 overexpression is closely associated with the suppression of p27 and the aggressiveness in NSCLC. It also could be a therapeutic target in NSCLC. (C) 2004 by American Society of Clinical Oncology.