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(American Journal of Pathology. 2002;161:207-216.)
© 2002 American Society for Investigative Pathology

Regular Articles

A Novel Target Gene, SKP2, within the 5p13 Amplicon That Is Frequently Detected in Small Cell Lung Cancers

Sana Yokoi^*, Kohichiroh Yasui^*, Fumiko Saito-Ohara^*, Katsumi Koshikawa, Toshihiko Iizasa, Takehiko Fujisawa, Takeo Terasaki, Akira Horii^¶, Takashi Takahashi, Setsuo Hirohashi and Johji Inazawa^*

From the Department of Molecular Cytogenetics,^*Medical Research Institute, Tokyo Medical and Dental University, Tokyo; the Department of Thoracic Surgery,Chiba University Graduate School of Medicine, Chiba; the Divisions of Molecular Oncology and Immunology,Aichi Cancer Center Research Institute, Nagoya; the Pathology Division,National Cancer Center Research Institute, Tokyo; and the Department of Molecular Pathology,^¶Tohoku University Graduate School of Medicine, Sendai, Japan

We investigated DNA copy-number aberrations in 22 cell lines derived from small cell lung cancers (SCLCs) using comparative genomic hybridization. A minimal common region at 5p13, within the 5p11-p13 amplicon that was most frequently involved, harbored the CDH6, PC4, and SKP2 genes. These three genes showed amplification and consequent overexpression in the SCLC cell lines. SKP2 positively regulates progression of cell cycle by targeting several regulators, such as the cell-cycle inhibitor p27^KIP1, for ubiquitin-mediated degradation. SKP2 was amplified in 7 (44%) of 16 primary SCLC tumors, and consequently overexpressed in 10 (83%) of the 12 of those tumors we examined. Expression levels of SKP2 protein were cell cycle-dependent in SCLC cells as well as in normal cells, and were correlated with the DNA copy-number of the gene. There was an inverse correlation between the expression of SKP2 and p27^KIP1 proteins. Down-regulation of SKP2 using an anti-sense oligonucleotide remarkably suppressed the growth of SCLC cells. Our results indicate that SKP2 is likely to be a target of the 5p13 amplification and to play an important role in the growth of SCLC cells.

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