Proteome analysis in normal liver, chronic hepatitis, liver cirrhosis and hepatocellular carcinoma-For a novel diagnosis, treatment and protection of hepatocellular carcinoma

正常肝脏、慢性肝炎、肝硬化和肝细胞癌的蛋白质组分析-肝细胞癌的新诊断、治疗和保护

基本信息

批准号：
15590654
负责人：
MASAKI Tsutomu
金额：
$ 2.24万
依托单位：
Kagawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590654/
关键词：
hepatocllular carcinoma cell cycle Cdk Cdk inhibitor p18^<INK4C>LECラット

项目摘要

Cyclins, cyclin-dependent kinases (Cdks), and Cdk inhibitors (CdkIs) are frequently altered in human cancer. p 18^<INK4C>, a member of the INK4 family among CdkIs, is a potential tumor suppressor gene product. However, the expression of p 18^<INK4C> in hepatocellular carcinoma (HCC) remains unknown. The aim of this study was to examine the expression of p18^<INK4C> in various liver diseases including HCC and to assess its clinical significance in HCC. To that end, we examined the expression of p 18^<INK4C> by immunohistochemistry in various liver diseases including 51 HCCs, and also studied the relationship among p 18^<INK4C> expression, the phosphorylation of retinoblastoma protein (pRb), and the activity level of Cdk4 and Cdk6. Immunohistochemical analysis revealed the frequent loss of p18^<INK4C> expression in HCC, especially in poorly differentiated HCC. The loss of p18^<INK4C> expression was shown to be associated with a poor prognosis as compared with that associated with p18^<INK4C>-positivity. Further, the kinas activity of Cdk4 was found to be higher in p18^<INK4C>-negative HCCs than in p 18^<INK4C>-positive HCCs. However, the level of Cdk6 activity was similar in the two groups of HCCs. In p18^<INK4C>-positive HCCs, p18^<INK4C> dominantly interacted with Cdk4 rather than with Cdk6. pRb phosphorylated at Ser 780 was detected more frequently in p18^<INK4C>-negative than in p 18^<INK4C>-positive HCCs. These data suggest that the loss of p18^<INK4C> expression may play a role in the differentiation and development of HCC through the upregulation of Cdk4 activity.

细胞周期蛋白，细胞周期蛋白依赖性激酶（CDKS）和CDK抑制剂（CDKI）在人类癌症中经常改变。 P 18^<ink4c>是CDKI中Ink4家族的成员，是潜在的肿瘤抑制基因产物。然而，肝细胞癌（HCC）中P 18^<ink4c>的表达仍然未知。这项研究的目的是检查包括HCC在内的各种肝病中p18^<ink4c>的表达，并评估其在HCC中的临床意义。为此，我们在包括51个HCC在内的各种肝病中通过免疫组织化学检查了P 18^<ink4c>的表达，还研究了P 18^<ink4c>表达之间的关系，视网膜细胞母细胞瘤蛋白（PRB）的磷酸化以及CDK4和CDK6的活性水平。免疫组织化学分析揭示了HCC中p18^<ink4c>表达的频繁损失，尤其是在分化较差的HCC中。与p18^<ink4c> - 阳性相比，p18^<ink4c>表达的损失与预后不良有关。此外，发现CDK4的kinas活性在p18^<ink4c>中的HCC中高于P 18^<ink4c> - 阳性HCC中的KINA活性。但是，两组HCC的CDK6活性水平相似。在p18^<ink4c> - 阳性HCC中，p18^<ink4c>主要与CDK4相互作用，而不是与CDK6相互作用。在p18^<ink4c>阴性中，在Ser 780处磷酸化的PRB比P 18^<ink4c> - 阳性HCC中的磷酸化更频繁。这些数据表明，通过CDK4活性的上调，p18^<ink4c>表达的损失可能在HCC的分化和发展中起作用。