Skomedal H, Kristensen G B, Lie A K, Holm R
Institute of Cancer Research, University of Oslo, Oslo, 0310, Norway.
Gynecol Oncol. 1999 May;73(2):223-8. doi: 10.1006/gyno.1999.5346.
The aims of this study were to study aberrant expression and coexpression of the cell cycle associated proteins TP53, p21, p27, cyclin D1, cdk4, RB, EGFR, and MDM2 in cervical carcinomas, to correlate protein alterations with histopathological and clinical parameters, and to evaluate whether these alterations provide prognostic information.
Seventy-four cervical carcinomas and 10 cases of normal cervical epithelium from patients with benign uterine leiomyomas were investigated immunohistochemically for aberrant expression of the cell cycle associated proteins using the biotin-streptavidin-peroxidase method and the OptiMax Plus automated cell staining system.
In normal cervical epithelium p27 immunostaining was identified in more than 50% of the cells, cdk4 in 5-50% of the cells, and EGFR in less than 5% of the cells, whereas no immunostaining for TP53, p21, MDM2, or cyclin D1 was detected. Positive RB protein staining was identified in all cases of normal cervical epithelium. RB protein staining was also identified in all carcinomas of the cervix uteri. Overexpression of p21 was found in 96% of the tumors, MDM2 in 35%, cdk4 in 69%, cyclin D1 in 3%, and EGFR in 20% of the tumors. A low level of p27 was observed in 65% of the cases. In a previous study, the TP53 protein level has been found to be elevated in 41 of the 74 (55%) cases included in this work. Significant coexpression was seen for TP53 and MDM2 (P = 0. 001); concording results were observed in 67% of the cases. There was no difference in aberrant expression or coexpression of any of the cell cycle regulatory proteins related to histological type, grade of differentiation, FIGO stage, or relapse-free survival.
The high number of cases showing increased levels of p21 and cdk4 and decreased levels of p27 suggests that these proteins may be important in the pathogenesis of cervical carcinoma. Furthermore aberrant expression of MDM2 in a smaller but significant fraction of cases indicates that these proteins could also be involved in the development of these cancers. Finally our results indicate that MDM2 may protect against HPV-induced TP53 protein degradation.
本研究旨在探讨细胞周期相关蛋白TP53、p21、p27、细胞周期蛋白D1、细胞周期蛋白依赖性激酶4（cdk4）、视网膜母细胞瘤蛋白（RB）、表皮生长因子受体（EGFR）和鼠双微体蛋白2（MDM2）在宫颈癌中的异常表达及共表达情况，将蛋白改变与组织病理学和临床参数相关联，并评估这些改变是否能提供预后信息。
采用生物素-链霉亲和素-过氧化物酶法及OptiMax Plus自动细胞染色系统，对74例宫颈癌及10例来自患有子宫平滑肌瘤患者的正常宫颈上皮组织进行免疫组织化学检测，以研究细胞周期相关蛋白的异常表达。
在正常宫颈上皮中，超过50%的细胞p27免疫染色阳性，5%-50%的细胞cdk4免疫染色阳性，不到5%的细胞EGFR免疫染色阳性，而未检测到TP53、p21、MDM2或细胞周期蛋白D1的免疫染色。所有正常宫颈上皮病例均可见RB蛋白阳性染色。子宫颈癌病例中也均见RB蛋白染色。96%的肿瘤中发现p21过表达，35%的肿瘤中MDM2过表达，69%的肿瘤中cdk4过表达，3%的肿瘤中细胞周期蛋白D1过表达，20%的肿瘤中EGFR过表达。65%的病例中观察到p27水平较低。在之前的一项研究中，本研究纳入的74例病例中有41例（55%）TP53蛋白水平升高。TP53与MDM2存在显著共表达（P = 0.001）；67%的病例结果一致。在组织学类型、分化程度、国际妇产科联盟（FIGO）分期或无复发生存方面，任何细胞周期调节蛋白的异常表达或共表达均无差异。
大量病例显示p21和cdk4水平升高而p27水平降低，提示这些蛋白可能在宫颈癌发病机制中起重要作用。此外，一小部分但有显著比例的病例中MDM2异常表达，表明这些蛋白也可能参与这些癌症的发生发展。最后，我们的结果表明MDM2可能防止人乳头瘤病毒（HPV）诱导的TP53蛋白降解。
