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S-phase kinase associated protein 2 (Skp2) is a member of an F-box family of substrate-recognition subunits of SCF ubiquitin-protein ligase complexes that has been implicated in the ubiquitin-mediated degradation of several key regulators of mammalian G1 progression, including the cyclin-dependent kinase inhibitor p27Kip1, a dosage-dependent tumor suppressor protein. The anti-sense effect was confirmed in two cell lines of oral cancer cells that also exhibited over-expression of the Skp2 protein. In this study, we examined the mechanism responsible for anti-sense-mediated growth inhibition of oral cancer cells in vitro and in vivo. Skp2-anti-sense treatment induced apoptosis characterized by an increase in the early apoptosis, fragmentation of nuclei and activation of caspase-3, -8 and -9. Moreover, the growth of xenograft tumors was markedly suppressed by Skp2-anti-sense treatment. Furthermore, histological specimen revealed apoptotic cell death was increased in Skp2-anti-sense treated tumors. Our results suggest that down-regulation of Skp2 appears to induce apoptosis in oral cancer cells, targeting this molecule could represent a promising new therapeutic approach for this type of cancer.

Low expression of p27(Kip1) is associated with disease progression and an unfavorable outcome in several malignancies including oral squamous cell carcinoma (SCC). In addition, p27(Kip1) protein is thought to be degraded by Skp2 (S-phase kinase-associated protein 2). The purpose of this study was to examine whether Skp2 expression can be a useful prognostic factor in oral SCC patients treated by UFT in combination with radiation. The Skp2 expression was investigated by immunohistochemistry in biopsy samples from 102 oral SCC patients, who were treated by UFT in combination with radiation. Associations of each expression with the clinicopathological characteristics and patient survival were also analyzed. A significant association was found between Skp2 expression and tumor size (p = 0.0462), cervical lymph node metastasis (p = 0.0209), therapeutic effect (p = 0.0490) and patient outcome (p = 0.0002). The 5-year survival rates of Skp2 high and low expression tumors were 40.5% and 78.5%, respectively, and this difference was significant (p = 0.0001) by log-rank test. Multivariate analysis revealed that reduced term of survival was related to high levels of Skp2 expression (p = 0.0001). These results suggest that Skp2 may be a useful prognostic factor in oral SCC patients treated by UFT in combination with radiation.