Sáez A, Sánchez E, Sánchez-Beato M, Cruz M A, Chacón I, Muñoz E, Camacho F I, Martínez-Montero J C, Mollejo M, García J F, Piris M A
Department of Pathology, Virgen de la Salud Hospital, Toledo, Spain.
Br J Cancer. 1999 Jul;80(9):1427-34. doi: 10.1038/sj.bjc.6690539.
Cell cycle progression is regulated by the combined action of cyclins, cyclin-dependent kinases (CDKs), and CDK-inhibitors (CDKi), which are negative cell cycle regulators. p27KIP1 is a CDKi key in cell cycle regulation, whose degradation is required for G1/S transition. In spite of the absence of p27KIP1 expression in proliferating lymphocytes, some aggressive B-cell lymphomas have been reported to show an anomalous p27KIP1 staining. We analysed p27KIP1 expression in a series of Diffuse Large B-cell Lymphoma (DLBCL), correlating it with the proliferative index and clinical outcome, to characterize the implications of this anomalous staining in lymphomagenesis in greater depth. For the above mentioned purposes, an immunohistochemical technique in paraffin-embedded tissues was employed, using commercially available antibodies, in a series of 133 patients with known clinical outcomes. Statistical analysis was performed in order to ascertain which clinical and molecular variables may influence outcome, in terms of disease-free survival (DFS) and overall survival (OS). The relationships between p27KIP1 and MIB-1 (Ki-67) were also tested. An abnormally high expression of p27KIP1 was found in lymphomas of this type. The overall correlation between p27KIP1 and MIB-1 showed there to be no significant relationship between these two parameters, this differing from observations in reactive lymphoid and other tissues. Analysis of the clinical relevance of these findings showed that a high level of p27KIP1 expression in this type of tumour is an adverse prognostic marker, in both univariate and multivariate analysis. These results show that there is abnormal p27KIP1 expression in DLBCL, with adverse clinical significance, suggesting that this anomalous p27KIP1 protein may be rendered non-functional through interaction with other cell cycle regulator proteins.
细胞周期进程受细胞周期蛋白、细胞周期蛋白依赖性激酶（CDK）和CDK抑制剂（CDKi）的共同作用调节，其中CDKi是细胞周期的负调节因子。p27KIP1是细胞周期调控中的关键CDKi，其降解是G1/S期转换所必需的。尽管增殖淋巴细胞中不存在p27KIP1表达，但据报道一些侵袭性B细胞淋巴瘤显示出异常的p27KIP1染色。我们分析了一系列弥漫性大B细胞淋巴瘤（DLBCL）中p27KIP1的表达情况，并将其与增殖指数和临床结果相关联，以更深入地探讨这种异常染色在淋巴瘤发生中的意义。为实现上述目的，我们采用免疫组织化学技术，使用市售抗体，对133例已知临床结果的患者的石蜡包埋组织进行检测。进行统计分析以确定哪些临床和分子变量可能影响无病生存期（DFS）和总生存期（OS）方面的结果。同时也检测了p27KIP1与MIB-1（Ki-67）之间的关系。在这类淋巴瘤中发现p27KIP1表达异常高。p27KIP1与MIB-1之间的总体相关性表明这两个参数之间无显著关系，这与反应性淋巴组织和其他组织中的观察结果不同。对这些发现的临床相关性分析表明，在单变量和多变量分析中，这类肿瘤中高水平的p27KIP1表达都是不良预后标志物。这些结果表明DLBCL中存在异常的p27KIP1表达，具有不良临床意义，提示这种异常的p27KIP1蛋白可能通过与其他细胞周期调节蛋白相互作用而丧失功能。
