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(American Journal of Pathology. 2004;165:2147-2155.)
© 2004 American Society for Investigative Pathology

Role of Cks1 Overexpression in Oral Squamous Cell Carcinomas

Cooperation with Skp2 in Promoting p27 Degradation

Shojiro Kitajima^*, Yasusei Kudo^*, Ikuko Ogawa, Tarig Bashir, Masae Kitagawa^*, Mutsumi Miyauchi^*, Michele Pagano and Takashi Takata^*

From the Department of Oral Maxillofacial Pathobiology,^* Division of Frontier Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; the Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima, Japan; and the Department of Pathology and NYU Cancer Institute, New York University School of Medicine, New York, New York

Down-regulation of p27 is frequently observed in various cancers due to an enhancement of its degradation. Skp2 is required for the ubiquitination and consequent degradation of p27 protein. Another protein called Cks1 is also required for p27 ubiquitination in the SCF^Skp2 ubiquitinating machinery. In the present study, we examined Cks1 expression and its correlation with p27 in oral squamous cell carcinoma (OSCC) derived from tongue and gingiva. By immunohistochemical analysis, high expression of Cks1 was present in 62% of OSCCs in comparison with 0% of normal mucosae. In addition, 65% of samples with low p27 expression displayed high Cks1 levels. Finally, Cks1 expression was well correlated with Skp2 expression and poor prognosis. To study the role of Cks1 overexpression in p27 down-regulation, we transfected Cks1 with or without Skp2 into OSCC cells. Cks1 transfection could not induce a p27 down-regulation by itself, but both Cks1 and Skp2 transfection strongly induced. Moreover, we inhibited Cks1 expression by small interference RNA (siRNA) in OSCC. Cks1 siRNA transfection induced p27 accumulation and inhibited the growth of OSCC cells. These findings suggest that Cks1 overexpression may play an important role for OSCC development through Skp2-mediated p27 degradation, and that Cks1 siRNA can be a novel modality of gene therapy.

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