REDUCED LEVELS OF THE CELL-CYCLE INHIBITOR P27(KIP1) IN EPITHELIAL DYSPLASIA AND CARCINOMA OF THE ORAL CAVITY

Recent studies have shown that the cyclin-dependent kinase (cdk) inhib itors play important roles in cell cycle progression in normal cells, Alterations in the cdk inhibitors also appear to be important in cance r development in a number of human tumors, p27(Kip1) is a member of th e CIP/KIP family of cdk inhibitors that negatively regulates cyclin-cd k complexes, Reduced levels of p27(Kip1) protein have been identified in a number of human cancers, and in some cases reduced p27(Kip1) is a ssociated with an increase in proliferative fraction. In the present s tudy, we examined p27(Kip1) protein by immunohistochemistry in 10 norm al and 36 dysplastic epithelia and in 8 squamous cell carcinomas from one anatomical site within the oral cavity, the floor of the mouth. Pr oliferative activity was assessed in serial sections by determining th e expression of the cell cycle proteins Ki-67 and cyclin A. p27(Kip1) protein was significantly reduced in oral dysplasias and carcinomas co mpared with that in normal epithelial controls, In addition, there was a significant reduction in p27(Kip1) protein between low- and high-gr ade dysplasias, suggesting that changes in p27(Kip1) expression may be an early event in oral carcinogenesis, There was increasing expressio n of Ki-67 and cyclin A proteins with increasingly severe grades of dy splasia compared with normal controls, Although there was a strong cor relation between Ki-67 and cyclin A scores (r(2) = 0.61) for all categ ories of disease, there was a weak negative correlation between Ki-67 and p27(Kip1) levels (r(2) = 0.29) and between cyclin A and p27(Kip1) levels (r(2) = 0.25), In conclusion, this study has found that a reduc tion in the proportion of cells expressing p27(Kip1) protein is freque ntly associated with oral dysplasia and carcinoma from the floor of th e mouth, Furthermore, reductions in p27(Kip1) levels are associated wi th increased cell proliferation, although other changes likely contrib ute to altered cell kinetics during carcinogenesis at this site.