title: Regulation of hepatic oval cell proliferation by adenoviral mediated hepatocyte growth factor gene transfer and signal transduction inhibitors.
abstract: OBJECTIVE
  To rescue patients with severe liver injury, it is critical to develop the efficient regulatory system of hepatic stem cell proliferation in vitro. Our aims are to examine whether combination of adenovirus-mediated hepatocyte growth factor (HGF) gene transfer with signal transduction inhibitors can regulate cell proliferation of oval cells.
  
  
  METHODS
  We examined the effects of treatment with adenoviral mediated HGF gene transfer and signal transduction inhibitors including LY294002, rapamycin and U0126 on proliferation OC/CDE22 hepatic oval cells and expression of signal transduction molecules.
  
  
  RESULTS
  Infection with pAxCAHGF expanded the cells by 8-fold at 2 days, by 18-fold at 3 days and by 55-fold at 4 days. The addition of inhibitors inhibited pAxCAHGF-induced cell proliferation by LY294002 or rapamycin (P < 0.01, each). U0126 also inhibited growth of hepatic oval cells (P < 0.01). pAxCAHGF treatment induced phosphorylation of AKT. Treatment with rapamycin resulted in enhanced phosphorylation of AKT, and phosphorylation of AKT was induced by pAxCAHGF plus U0126.
  
  
  CONCLUSIONS
  Autocrine expression of HGF with signal transduction inhibitors can regulate proliferation of OC/CDE22 hepatic oval cells. In addition, the AKT pathway is important for HGF-stimulated hepatic oval cell proliferation.
authors.affiliation: Division of Molecular and Genetic Medicine, Department of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago 683-8504, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kato
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimomura
authors.forename: Rie
authors.initials: R
authors.lastname: Murai
authors.forename: Kazue
authors.initials: K
authors.lastname: Gonda
authors.forename: Kyoko
authors.initials: K
authors.lastname: Ishii
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Takamasa
authors.initials: T
authors.lastname: Kanbe
authors.forename: Ko-ichi
authors.initials: K
authors.lastname: Hashiguchi
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Sakabe
authors.forename: Kazue
authors.initials: K
authors.lastname: Takubo
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Okano
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuchiya
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Hoshikawa
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kurimasa
authors.forename: Goshi
authors.initials: G
authors.lastname: Shiota
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D002070:Butadienes / Q000494:pharmacology; D018929:Cell Culture Techniques; D049109:Cell Proliferation; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018014:Gene Transfer Techniques; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D001616:beta-Galactosidase / Q000032:analysis / Q000378:metabolism
chemical_list: D002070:Butadienes; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D009570:Nitriles; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D017228:Hepatocyte Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D001616:beta-Galactosidase; D020123:Sirolimus