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(American Journal of Pathology. 2004;165:175-180.)
© 2004 American Society for Investigative Pathology

Amplification and Overexpression of SKP2 Are Associated with Metastasis of Non-Small-Cell Lung Cancers to Lymph Nodes

Sana Yokoi^*, Kohichiroh Yasui^*, Miki Mori^*, Toshihiko Iizasa, Takehiko Fujisawa and Johji Inazawa^*

From the Department of Molecular Cytogenetics,^* Graduate School of Biomedical Science, Medical Research Institute, Tokyo Medical and Dental University, Tokyo; Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi; and the Department of Thoracic Surgery, Chiba University Graduate School of Medicine, Chiba, Japan

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.

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