Molecular pathological analysis of the expression of receptor-type tyrosine kinase in hepatocellular carcinoma

受体型酪氨酸激酶在肝细胞癌中表达的分子病理学分析

• 批准号: 10670211
• 负责人: SEKINE Ichiro
• 金额: $ 2.05万
• 依托单位: Nagasaki University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670211/
• 关键词: Hepatocellular carcinoma; Receptor-type tyrosine kinase; Oval cell; Preneoplastic lesic; Degenerated PCR

BACKGROUND: Growth factor receptor tyrosine kinase signaling is known to play key roles in regulating growth and differentiation of normal hepatocytes, however, the specific receptor-type tyrosine kinases (RTKs) involved in hepatocarcinogenesis remain undetermined. AIMS: The aim of this study was to characterize the expression of these receptors in different stages of rat liver carcinogenesis, METHODS: We analyzed the expression profile of RTK genes in rat normal liver and diethylnitrosamine-induced hepatocellular carcinoma (HCC) tissues using a homology cloning method With degenerated primers. In situ hybridization, immunohistochemical staining, and RT-PCR were performed to analyze the cell type-specific expression of target RTKs during hepato-carcinogenesis. RESULTS: sequence analysis of 459 clones identified 23 different RTK genes. The Tie-2, c-Met, and Flk-1 genes were the most abundant RTKs expressed in rat HCC. Immunohistochemical and in situ hybridization studies showed overexpression of c-Met and Flk-1 in preneoplastic lesions as well as neoplastic lesions of HCC. Furthermore, Flk-1 mRNA expression was detected by RT-PCR in a hepatoma cell line of F344 rats. Tie-2 was expressed in endothelial cells of tumor vessels as well as in so-called oval cells, which are thought to be liver stem cells. CONCLUSION: Our results indicated the important role of c-Met, Tie-2 and VEGF/Flk-1 signals in different stages of hepatocarcinogenesis, suggesting specific and interdependent RTK expression during hepatocarcinogenesis.

背景：已知生长因子受体酪氨酸激酶信号在调节正常肝细胞的生长和分化中起关键作用，然而，参与肝癌发生的特异性受体型酪氨酸激酶（RTKs）仍不确定。目的：研究RTK基因在大鼠肝癌发生不同阶段的表达特征。方法：采用同源克隆方法，用退化引物分析RTK基因在大鼠正常肝脏和二乙基亚硝胺诱导的肝细胞癌（HCC）组织中的表达谱。采用原位杂交、免疫组织化学染色和RT-PCR分析肝癌发生过程中靶rtk的细胞类型特异性表达。结果：对459个克隆进行序列分析，鉴定出23个不同的RTK基因。Tie-2、c-Met和Flk-1基因是大鼠HCC中表达最丰富的rtk基因。免疫组织化学和原位杂交研究显示c-Met和Flk-1在肝癌癌前病变和肿瘤病变中过表达。RT-PCR检测Flk-1 mRNA在F344大鼠肝癌细胞系中的表达。Tie-2在肿瘤血管内皮细胞以及被认为是肝干细胞的所谓卵圆细胞中表达。结论：我们的研究结果提示c-Met、Tie-2和VEGF/Flk-1信号在肝癌发生的不同阶段具有重要作用，提示RTK在肝癌发生过程中的表达具有特异性和依赖性。

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