Zagzag David, Blanco Cy, Friedlander David R, Miller Douglas C, Newcomb Elizabeth W
Department of Pathology and the New York University Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
Hum Pathol. 2003 Jan;34(1):48-53. doi: 10.1053/hupa.2003.54.
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.
众多研究探讨了p27KIP1表达在人类癌症中的预后意义，结果表明其表达降低往往是与较差生存率相关的独立预后因素。然而，p27KIP1表达在胶质瘤中的预后价值尚未完全明确。为进一步解决这一问题，我们采用蛋白质印迹分析和免疫组织化学方法，评估了50例星形细胞瘤中p27KIP1蛋白表达与包括年龄、肿瘤分级、MIB-1增殖指数及患者生存率等临床病理参数之间的关系。9例非肿瘤性脑组织标本中p27KIP1蛋白表达水平作为对照。16例高级别星形细胞瘤采用蛋白质印迹法分析，26例高级别星形细胞瘤采用免疫组织化学法分析p27KIP1蛋白表达水平。无论采用何种技术检测p27KIP1，约50%的高级别肿瘤为低表达者，另外50%为高表达者。因此，p27KIP1的表达与肿瘤分级无关。p27KIP1表达缺失常与增殖活性增加相关。我们在16例高级别星形细胞瘤中采用MIB-1免疫染色检测肿瘤细胞增殖率，以确定p27KIP1表达与增殖之间是否存在负相关。未发现p27KIP1表达与MIB-1标记指数或患者生存率之间存在相关性。采用免疫组织化学方法，我们注意到胶质母细胞瘤中p27KIP1的染色模式主要位于勾勒坏死区域的假栅栏状细胞中。由于p27KIP1可被缺氧上调，这种染色模式与我们观察到的缺氧诱导因子1α主要在坏死区周围的假栅栏状肿瘤细胞中表达相一致。研究表明，高水平的p27KIP1可防止缺氧细胞凋亡。因此，胶质瘤中p27KIP1高水平的维持可能源于肿瘤内存在的缺氧微环境。未发现p27KIP1表达与所检测的任何临床病理参数之间存在相关性，包括患者年龄和肿瘤分级（胶质瘤患者生存的两个最强预测因素）。
