Amplification and overexpression of SKP2 are associated with metastasis of non-small-cell lung cancers to lymph nodes

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Survival
  • Collagen / metabolism
  • Drug Combinations
  • Gene Amplification
  • Gene Expression
  • Humans
  • In Situ Hybridization, Fluorescence
  • Laminin / metabolism
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Lymph Nodes / pathology*
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Oligonucleotides, Antisense / pharmacology
  • Polymerase Chain Reaction
  • Proteoglycans / metabolism
  • S-Phase Kinase-Associated Proteins / genetics*
  • S-Phase Kinase-Associated Proteins / metabolism*


  • Drug Combinations
  • Laminin
  • Oligonucleotides, Antisense
  • Proteoglycans
  • S-Phase Kinase-Associated Proteins
  • matrigel
  • Collagen