Peng S Y, Chou S P, Hsu H C
Graduate Institute of Pathology, College of Medicine, National Taiwan University.
J Hepatol. 1998 Aug;29(2):281-9. doi: 10.1016/s0168-8278(98)80014-7.
BACKGROUND/AIMS: The major regulatory events leading to cell proliferation occur in the G1 phase of cell cycle, and the deranged expression of G1 cyclins is related to oncogenesis. In this study, we analyzed the aberrant expressions of cyclins D1 and E, and their role in hepatocellular carcinoma.
We examined paired hepatocellular carcinoma and liver RNAs taken from 71 patients who had been followed for more than 4 years after tumor resection, using reverse transcription-polymerase chain reaction supplemented with Northern blotting and immunohistochemistry. The genetic alterations of the p53 gene were also studied.
Downregulation of cyclin D1 mRNA was detected in 29 hepatocellular carcinomas (40.8%), while overexpression was detected in only 4 hepatocellular carcinomas (5.6%). Downregulation of cyclin D1 was associated significantly with large hepatocellular carcinomas (p=0.0006) and poorly differentiated (grades III-IV) hepatocellular carcinoma (p=0.057), but not seen in any of 15 minute hepatocellular carcinomas (< or =2.5 cm in size). Cyclin E mRNA was overexpressed in 40 hepatocellular carcinomas, regardless of tumor size. Overexpression of cyclin E was significantly associated with poorly differentiated and invasive hepatocellular carcinoma (p=0.001 and p=0.015, respectively). Downregulation of cyclin D1 and overexpression of cyclin E were significantly associated with the p53 mutation (p=0.023 and p=0.005, respectively). Hepatocellular carcinomas expressing both downregulation of cyclin D1 and overexpression of cyclin E had the worst 4-year survival (p<0.03), and higher frequencies of the p53 mutation (p<0.001), large hepatocellular carcinoma (p<0.001), and invasive tumor (p<0.01).
The deranged expressions of G1 cyclins correlate with the p53 mutation, tumor progression, and tumor biologic behavior of hepatocellular carcinoma. Overexpression of cyclin E occurs early, and downregulation of cyclin D1 late in hepatocellular carcinoma growth.
背景/目的：导致细胞增殖的主要调控事件发生在细胞周期的G1期，G1期细胞周期蛋白的表达紊乱与肿瘤发生有关。在本研究中，我们分析了细胞周期蛋白D1和E的异常表达及其在肝细胞癌中的作用。
我们使用逆转录-聚合酶链反应，并辅以Northern印迹法和免疫组织化学，检测了71例肿瘤切除后随访超过4年的患者的配对肝细胞癌和肝脏RNA。同时也研究了p53基因的遗传改变。
在29例肝细胞癌（40.8%）中检测到细胞周期蛋白D1 mRNA下调，而仅在4例肝细胞癌（5.6%）中检测到过表达。细胞周期蛋白D1下调与大肝细胞癌（p = 0.0006）和低分化（III-IV级）肝细胞癌（p = 0.057）显著相关，但在15例微小肝细胞癌（≤2.5 cm）中均未发现。无论肿瘤大小，细胞周期蛋白E mRNA在40例肝细胞癌中过表达。细胞周期蛋白E过表达与低分化和侵袭性肝细胞癌显著相关（分别为p = 0.001和p = 0.015）。细胞周期蛋白D1下调和细胞周期蛋白E过表达与p53突变显著相关（分别为p = 0.023和p = 0.005）。同时表达细胞周期蛋白D1下调和细胞周期蛋白E过表达的肝细胞癌4年生存率最差（p < 0.03），p53突变频率更高（p < 0.001），大肝细胞癌（p < 0.001）和侵袭性肿瘤（p < 0.01）的发生率也更高。
G1期细胞周期蛋白的表达紊乱与p53突变、肿瘤进展和肝细胞癌的肿瘤生物学行为相关。细胞周期蛋白E过表达在肝细胞癌生长早期出现，而细胞周期蛋白D1下调在晚期出现。
