Ito Y, Matsuura N, Sakon M, Miyoshi E, Noda K, Takeda T, Umeshita K, Nagano H, Nakamori S, Dono K, Tsujimoto M, Nakahara M, Nakao K, Taniguchi N, Monden M
Department of Surgery II, Osaka University Medical School, Osaka, Japan.
Hepatology. 1999 Jul;30(1):90-9. doi: 10.1002/hep.510300114.
Expression of cell-cycle modulators at the G1-S boundary, retinoblastoma gene product (pRb), p21, p16, p27, p53, cyclin D1, and cyclin E was investigated with 104 hepatocellular carcinomas (HCC), as well as 90 of their adjacent noncancerous lesions and 9 normal liver control specimens. The labeling indices (LI) of pRb, p21, p16, and p27 were higher in HCC lesions than in the adjacent noncancerous lesions and normal controls. Especially, p27 LI in noncancerous lesions was significantly higher than that in normal livers (P =.011). Aberrant p53 expression and cyclin D1 and E overexpression were observed exclusively in HCC lesions. pRb was positive in 85.6% of the HCC cases and was not related to any clinicopathological parameters. The p21 LI was generally low (average, 5.5 +/- 9.8). Although a negative regulator, p21 LI was higher in cases with intrahepatic metastasis (P =.0359). The p16 LI was significantly decreased (P =.0121) in cases with advanced stage. p27 LI was significantly decreased in cases with portal invasion (P =.0409), poor differentiation (P <.0001), larger size (P =.0421), and intrahepatic metastasis (P =.0878, borderline significance). On the other hand, aberrant p53 expression showed positive relationships with poor differentiation (P =.0004) and Ki-67 LI (P =. 0047). Cyclin D1 overexpression was found in 32.6% of the cases and occurred more frequently in those with high Ki-67 LI (P =.0032), pRb expression (P =.0202), poor differentiation (P =.0612, borderline significance), and intrahepatic metastasis (P =.0675, borderline significance). Cyclin E was overexpressed in 35.5% and had positive relationships with Ki-67 LI (P =.0269) and stage (P =.0125). In univariate analysis, cases with p27 LI < 50 (P =.0004), cyclin D1 overexpression (P =.0041), and cyclin E overexpression (P =.0572, borderline significance) showed poorer outcomes for disease-free survival (DFS). In multivariate analysis, p27 expression could be recognized as an independent prognostic marker for DFS. These findings suggest that in HCC: 1) p27 is active against HCC progression in early phases and, possibly, hepatocarcinogenesis as a negative regulator and can be a novel prognostic marker for DFS; and 2) cyclin D1 predominantly works for cell-cycle progression at the G1-S boundary.
对104例肝细胞癌（HCC）及其90例癌旁非癌组织和9例正常肝对照标本，研究了细胞周期调节因子在G1 - S边界的表达情况，包括视网膜母细胞瘤基因产物（pRb）、p21、p16、p27、p53、细胞周期蛋白D1和细胞周期蛋白E。HCC病变中pRb、p21、p16和p27的标记指数（LI）高于癌旁非癌组织和正常对照。特别是，非癌组织中的p27 LI显著高于正常肝脏（P = 0.011）。p53异常表达以及细胞周期蛋白D1和E过表达仅在HCC病变中观察到。pRb在85.6%的HCC病例中呈阳性，且与任何临床病理参数均无关。p21 LI一般较低（平均为5.5±9.8）。尽管p21是一种负调节因子，但在肝内转移病例中其LI较高（P = 0.0359）。在晚期病例中，p16 LI显著降低（P = 0.0121）。在门静脉侵犯（P = 0.0409）、低分化（P < 0.0001）、肿瘤较大（P = 0.0421）和肝内转移（P = 0.0878，临界显著性）的病例中，p27 LI显著降低。另一方面，p53异常表达与低分化（P = 0.0004）和Ki-67 LI（P = 0.0047）呈正相关。在32.6%的病例中发现细胞周期蛋白D1过表达，在Ki-67 LI高（P = 0.0032）、pRb表达（P = 0.0202）、低分化（P = 0.0612，临界显著性）和肝内转移（P = 0.0675，临界显著性）的病例中更常见。细胞周期蛋白E在35.5%的病例中过表达，与Ki-67 LI（P = 0.0269）和分期（P = 0.0125）呈正相关。单因素分析中，p27 LI < 50（P = 0.0004）、细胞周期蛋白D1过表达（P = 0.0041）和细胞周期蛋白E过表达（P = 0.0572，临界显著性）的病例无病生存期（DFS）较差。多因素分析中，可以将p27表达识别为DFS的独立预后标志物。这些发现表明，在HCC中：1）p27作为负调节因子在早期阶段对HCC进展及可能的肝癌发生具有抑制作用，可作为DFS的新型预后标志物；2）细胞周期蛋白D1主要在G1 - S边界促进细胞周期进程。
