Expression of p27KIP1 in human gliomas: relationship between tumor grade, proliferation index, and patient survival.

Numerous studies examining the prognostic significance of p27KIP1 expression in human cancer have shown that decreased expression often is an independent prognostic factor associated with worse survival. However, the prognostic value of p27KIP1 expression in gliomas is less well established. To further address this issue, we evaluated the relationship between p27KIP1 protein expression in a series of 50 astrocytomas with clinicopathologic parameters including age, tumor grade, MIB-1 proliferation index, and patient survival using both Western blot analysis and immunohistochemistry. The level of p27KIP1 protein expression in 9 nonneoplastic brain tissue specimens served as a control. Sixteen high-grade astrocytomas were analyzed by Western blot, and 26 high-grade astrocytomas were analyzed by immunohistochemistry for levels of p27KIP1 protein expression. Regardless of the technique used to measure p27KIP1, approximately 50% of the high-grade tumors were low expressors and the other 50% were high expressors. Thus, expression of p27KIP1 was independent of tumor grade. Loss of p27KIP1 expression is often associated with an increase in proliferative activity. We measured the rate of tumor cell proliferation using MIB-1 immunostaining in 16 high-grade astrocytomas to determine whether there was an inverse correlation between p27KIP1 expression and proliferation. No correlation between p27KIP1 expression and MIB-1 labeling index or patient survival was found. Using immunohistochemistry, we noted that the staining pattern of p27KIP1 in glioblastomas was mainly in the pseudopalisading cells that outline areas of necrosis. Because p27KIP1 can be up-regulated by hypoxia, this staining pattern would be consistent with our observation that hypoxia-inducible factor 1alpha is expressed primarily in pseudopalisading tumor cells around necrotic zones. It has been shown that a high level of p27KIP1 prevents apoptosis in hypoxic cells. Thus, maintenance of high levels of p27KIP1 in gliomas could result from the hypoxic microenvironment present within the tumor. No correlation was found between p27KIP1 expression and any of the clinicopathologic parameters tested, including patient age and tumor grade, the 2 strongest predictors of survival among glioma patients.