title: Distinctive gene expression of receptor-type tyrosine kinase families during rat hepatocarcinogenesis.
abstract: Growth factor receptor tyrosine kinase signaling plays key roles in regulating growth of normal hepatocytes, however, which receptor-type tyrosine kinase (RTK) is involved in hepatocarcinogenesis remains undetermined. The aim of this study was to characterize the expression of these receptors in different stages of rat liver carcinogenesis. We compared the expression profile of RTK genes in rat normal liver and diethylnitrosamine-induced hepatoma 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 the chemically-induced hepatocarcinogenesis. Sequence analysis of 459 clones identified 23 different RTK genes. The Tie-2, c-Met, and Flk-1 genes were the most abundant RTK genes cloned in rat hepatoma compared to normal liver. In situ hybridization and immunohistochemical studies showed overexpression of c-Met and Flk-1 in GST-P positive preneoplastic lesions as well as neoplastic lesions. Tie-2 was expressed not only in endothelial cells but also in so-called oval cells, which are thought to be liver stem cells. Tie-2 ligand, angiopointin-1, mRNA was detected in both normal livers and hepatoma cells/tissues. In contrast, angiopoietin-2 mRNA was detected only in hepatoma tissues. These results indicate that c-Met, Tie-2 and Flk-1 signals play important roles in different stages of chemically-induced hepatocarcinogenesis. Distinctive gene expression of RTK may contribute to epigenic implication of hepatoma formation.
authors.affiliation: Department of Surgery II, Nagasaki University School of Medicine, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kuroda
authors.forename: Akira
authors.initials: A
authors.lastname: Ohtsuru
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Futakuchi
authors.forename: Yujo
authors.initials: Y
authors.lastname: Kawashita
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagayama
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Fukuda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Namba
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Shirai
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanematsu
authors.forename: Shunichi
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015139:Blotting, Southern; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D003001:Cloning, Molecular; D004052:Diethylnitrosamine / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D008099:Liver / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D012334:RNA, Neoplasm; D004052:Diethylnitrosamine; D020794:Receptor Protein-Tyrosine Kinases