Ito T, Shiraki K, Sugimoto K, Yamanaka T, Fujikawa K, Ito M, Takase K, Moriyama M, Kawano H, Hayashida M, Nakano T, Suzuki A
First Department of Internal Medicine, Mie University School of Medicine, Tsu, Japan.
Hepatology. 2000 May;31(5):1080-5. doi: 10.1053/he.2000.6496.
Survivin is a recently described inhibitor of apoptosis. Because suppression of apoptosis is important for carcinogenesis and tumor growth, we investigated the expression and function of survivin in human hepatocellular carcinomas (HCCs). We have shown that 4 HCC cell lines and 7 out of 8 human HCC tissues expressed survivin messenger RNA (mRNA), whereas expression of survivin mRNA was not detected in normal liver and nontumor areas of these tissues using the reverse transcription polymerase chain reaction. Survivin was detected primarily in the nucleus by immunofluorescence staining of HCC cells. In addition, 14 of 20 (70%) HCC tissues showed positive nuclear staining for survivin, whereas nontumor tissues showed little detectable staining by immunohistochemistry. Survivin expression strongly correlated with the proliferation index but not significantly with the apoptosis index in HCC tissues. Therefore, we performed cell cycle analysis after survivin transfection and showed that overexpression of survivin resulted in a decrease in the G(0)/G(1) phase and an increase in the S phase in all 4 HCC cell lines. Furthermore, we have found that survivin interacted with cyclin-dependent kinase 4 (Cdk4) and overexpression of survivin released p21(WAF1/Cip1) (p21) from Cdk4. From these results, we conclude that survivin promotes cell proliferation by interacting with Cdk4 and releasing p21 from Cdk4. This may play an important role in carcinogenesis and progression of human HCCs.
生存素是最近发现的一种凋亡抑制因子。由于凋亡抑制对肿瘤发生和肿瘤生长至关重要，我们研究了生存素在人类肝细胞癌（HCC）中的表达及功能。我们发现，4种肝癌细胞系以及8例人类肝癌组织中的7例表达生存素信使核糖核酸（mRNA），而采用逆转录聚合酶链反应在这些组织的正常肝组织及非肿瘤区域未检测到生存素mRNA的表达。通过肝癌细胞的免疫荧光染色发现，生存素主要定位于细胞核。此外，20例肝癌组织中有14例（70%）生存素细胞核染色呈阳性，而通过免疫组织化学检测，非肿瘤组织几乎未检测到染色。在肝癌组织中，生存素表达与增殖指数密切相关，但与凋亡指数无显著相关性。因此，我们在转染生存素后进行细胞周期分析，结果显示，在所有4种肝癌细胞系中，生存素过表达导致G(0)/G(1)期细胞减少，S期细胞增加。此外，我们发现生存素与细胞周期蛋白依赖性激酶4（Cdk4）相互作用，生存素过表达使p21（WAF1/Cip1）（p21）从Cdk4中释放出来。基于这些结果，我们得出结论：生存素通过与Cdk4相互作用并使p21从Cdk4中释放出来促进细胞增殖。这可能在人类肝癌的发生和发展中起重要作用。
