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

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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.