Naka T, Toyota N, Kaneko T, Kaibara N
First Department of Surgery, Faculty of Medicine, Tottori University, Japan.
Anticancer Res. 1998 Jan-Feb;18(1B):555-64.
Many genes participate in the regulation of cell cycle progression from G1 to S phase. Functional loss of one or more of these genes has been reported to be associated with carcinogenesis and/or tumor progression and poor prognosis in many cancers. In a series of 126 patients with hepatocellular carcinoma (HCC), we immunohistochemically evaluated tumor expression of the cell cycle-related gene protein products of Rb, p21 (WAF1), and p53. Positive immunostaining for Rb, p21, and mutant p53 protein was detected in 58%, 33%, and 37% of the tumors, respectively. The proportion of HCCs exhibiting aberrant p53 protein expression increased significantly with advancing stage of disease (p < 0.001), poorer histological classification of differentiation (p < 0.01), and increasing tumor size (p < 0.01). A decrease in the proportion of HCCs expressing p21 protein was also associated with advancing clinical stage of disease (p < 0.01), and larger tumor size (p < 0.05). The only clinicopathological feature found to be associated with Rb status, was intrahepatic metastasis, which occurred with a higher frequency in HCCs exhibiting positive immunoreactivity for Rb protein expression (p < 0.05). Multivariate survival analysis revealed that, amongst the protein products of the different genes evaluated, only positive immunostaining for aberrant p53 protein expression served as an independent prognostic indicator, being significantly associated with worse survival in patients with HCC (p = 0.023). Analysis for relationships between gene products showed an inverse correlation between expression of aberrant p53 protein and p21 protein (p < 0.01), and also an inverse correlation between p21 protein and Rb protein expression (p < 0.05) in these cases of HCC. These findings demonstrate that positive immunostaining for mutant p53 protein expression is a significant indicator of tumor progression and poor prognosis, confirm that p21 protein expression is induced in a p53-dependent manner, and suggest that Rb protein expression may be regulated to some extent by p21 in HCC.
许多基因参与细胞周期从G1期到S期进程的调控。据报道，这些基因中一个或多个基因的功能丧失与多种癌症的致癌作用、肿瘤进展及不良预后相关。在一组126例肝细胞癌（HCC）患者中，我们采用免疫组织化学方法评估了细胞周期相关基因Rb、p21（WAF1）和p53蛋白产物在肿瘤中的表达情况。分别在58%、33%和37%的肿瘤中检测到Rb、p21和突变型p53蛋白的阳性免疫染色。显示异常p53蛋白表达的HCC比例随着疾病分期的进展（p<0.001）、组织学分化程度较差（p<0.01）以及肿瘤大小增加（p<0.01）而显著增加。表达p21蛋白的HCC比例降低也与疾病临床分期的进展（p<0.01）和肿瘤较大（p<0.05）相关。发现与Rb状态相关的唯一临床病理特征是肝内转移，其在Rb蛋白表达呈阳性免疫反应的HCC中发生频率更高（p<0.05）。多因素生存分析显示，在所评估的不同基因的蛋白产物中，只有异常p53蛋白表达的阳性免疫染色作为独立的预后指标，与HCC患者较差的生存率显著相关（p=0.023）。对基因产物之间关系的分析显示，在这些HCC病例中，异常p53蛋白表达与p21蛋白表达呈负相关（p<0.01），p21蛋白与Rb蛋白表达也呈负相关（p<0.05）。这些发现表明，突变型p53蛋白表达的阳性免疫染色是肿瘤进展和不良预后的重要指标，证实p21蛋白表达是以p53依赖的方式诱导的，并提示在HCC中Rb蛋白表达可能在一定程度上受p21调控。
