Yokoi Sana, Yasui Kohichiroh, Mori Miki, Iizasa Toshihiko, Fujisawa Takehiko, Inazawa Johji
Department of Molecular Cytogenetics, Graduate School of Biomedical Science, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Am J Pathol. 2004 Jul;165(1):175-80. doi: 10.1016/S0002-9440(10)63286-5.
SKP2, an F-box protein constituting the substrate recognition subunit of the SCF(SKP2) ubiquitin ligase complex, is implicated in ubiquitin-mediated degradation of the cyclin-dependent kinase inhibitor p27(KIP1). Our earlier studies revealed SKP2 as a target gene within the 5p13 amplicon that is often seen in small-cell lung cancers. In the present study we examined amplification status and expression levels of SKP2 in non-small-cell lung cancer (NSCLC) and investigated its clinicopathological significance in this type of tumor because amplification of DNA at 5p13 is observed frequently in NSCLCs as well as in small-cell lung cancers. SKP2 exhibited amplification in 5 (20%) of 25 cell lines derived from NSCLC, and the transcript was overexpressed in 11 (44%) of the 25 lines. Moreover, expression of SKP2 was up-regulated significantly in 60 primary NSCLC tumors as compared to nontumorous lung tissues (P < 0.0001). Elevated expression of SKP2 correlated significantly with positive lymph node metastasis (P = 0.007), with stage II or higher of the international TNM classification (P = 0.014), with poor or moderate differentiation (P < 0.001), and with the presence of squamous cell carcinoma (P = 0.037). Reduction of SKP2 expression by transfection of an anti-sense oligonucleotide inhibited invasion and migration of NSCLC cells in culture. Our results suggest that SKP2 may be involved in progression of NSCLC, and that targeting this molecule could represent a promising therapeutic option.
SKP2是一种F-box蛋白，构成SCF（SKP2）泛素连接酶复合体的底物识别亚基，参与细胞周期蛋白依赖性激酶抑制剂p27（KIP1）的泛素介导降解。我们早期的研究表明，SKP2是5p13扩增子内的一个靶基因，在小细胞肺癌中经常可见。在本研究中，我们检测了非小细胞肺癌（NSCLC）中SKP2的扩增状态和表达水平，并研究了其在这类肿瘤中的临床病理意义，因为在NSCLC以及小细胞肺癌中均频繁观察到5p13处的DNA扩增。在25个源自NSCLC的细胞系中，有5个（20%）出现SKP2扩增，25个细胞系中有11个（44%）转录本过表达。此外，与非肿瘤肺组织相比，60例原发性NSCLC肿瘤中SKP2的表达显著上调（P < 0.0001）。SKP2表达升高与阳性淋巴结转移显著相关（P = 0.007），与国际TNM分期II期或更高显著相关（P = 0.014），与低分化或中分化显著相关（P < 0.001），与鳞状细胞癌的存在显著相关（P = 0.037）。通过转染反义寡核苷酸降低SKP2表达可抑制培养的NSCLC细胞的侵袭和迁移。我们的结果表明，SKP2可能参与NSCLC的进展，靶向该分子可能是一种有前景的治疗选择。
