Insufficient effect of p27(KIP1) to inhibit cyclin D1 in human esophageal cancer in vitro.

The cell cycle is controlled by protein complexes composed of cyclins and cyclin-dependent kinases. p27KIP1 (p27) is one of the Kip/Cip family cyclin-dependent kinase inhibitory proteins which negatively regulate cell cycle progression, and have been proposed as candidate tumor suppressor genes. To examine the role of p27 in the development of human esophageal squamous cell carcinoma (ESCC), we performed Western blot and immunoprecipitation analyses of the levels of expression of p27 protein in a series of ESCC cell lines. This protein was expressed at various levels in these cell lines during exponential growth. p27 level was significantly associated with that of cyclin D1, but not of cyclin E. Further cell cycle synchronization studies demonstrated that p27 was free or bound with affinity to cyclin E-CDK2 more than to cyclin D1-CDK4 or cyclin D1-CDK6. It is known that overexpression of cyclin D1 rather than cyclin E is involved in the pathogenesis of ESCC. Our findings indicated that high expression of p27 throughout the G1 to S phase may inhibit more likely cyclin E, than cyclin D1, which promotes tumor growth of esophageal squamous cell carcinoma.

Positive correlation between p27Kip1 expression and progression of human esophageal squamous cell carcinoma.

p27Kip1, one of the cyclin-dependent kinase (CDK) inhibitors (CDKIs), blocks progression from G1 to S phase by binding cyclin D1-CDK4 and/or cyclin E-CDK2 and inhibiting their activities. Reflecting the function of p27 as a CDKI in vitro, a reduced expression of protein p27 has recently been reported to be associated with tumor aggressiveness in some types of human cancers. In the present study, we examined the relationships between immunohistochemically detected expression of p27, cyclin D1, cyclin E proteins and clinicopathological findings in 77 patients with esophageal squamous cell carcinoma (SCC). Using specific monoclonal antibodies to p27, cyclin DI and cyclin E proteins, positive immunostaining in the nuclei was observed in 32.5% (25/77), 27.3% (21177) and 29.6% (21/71) of patients, respectively. There were no statistically significant relationships among the expressions of these 3 proteins. Using the Kaplan-Meier's method, p27 and cyclin D1 expressions were found to be independently associated with poor prognosis. When all parameters were combined into a multivariate regression analysis using the Cox model, the expressions of p27 and cyclin D1 retained a predictive value for survival. In contrast to former reports supporting a tumor-suppressive function of p27, our results suggest that altered expression of p27 and cyclin D1 may be associated with the progression of human esophageal SCC, in which cyclin E may well not play any central role.