title: Amplification and overexpression of SKP2 are associated with metastasis of non-small-cell lung cancers to lymph nodes.
abstract: 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.
authors.affiliation: 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.
authors.forename: Sana
authors.initials: S
authors.lastname: Yokoi
authors.forename: Kohichiroh
authors.initials: K
authors.lastname: Yasui
authors.forename: Miki
authors.initials: M
authors.lastname: Mori
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Iizasa
authors.forename: Takehiko
authors.initials: T
authors.lastname: Fujisawa
authors.forename: Johji
authors.initials: J
authors.lastname: Inazawa
mesh_terms: D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D005784:Gene Amplification; D015870:Gene Expression; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007797:Laminin / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008198:Lymph Nodes / Q000473:pathology*; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011509:Proteoglycans / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D004338:Drug Combinations; D007797:Laminin; D016376:Oligonucleotides, Antisense; D011509:Proteoglycans; D044786:S-Phase Kinase-Associated Proteins; C059485:matrigel; D003094:Collagen