title: Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma.
abstract: Hepatocyte growth factor-scatter factor (HGF-SF) is a potent hepatic mitogen yet inhibits hepatocellular carcinoma (HCC) cell growth in vitro. Insulin-like growth factor I (IGF-I) is a pleiotropic growth factor shown to be important in cell growth and differentiation in other tumors. We hypothesized that IGF-I may play a role in regulating HGF-SF activity and HCC progression. Using an in vivo model of HCC, we showed elevated IGF-I messenger RNA (mRNA) expression in normal liver from tumor-burdened animals in the absence of changes in circulating IGF-I levels. Analysis of IGF-I receptor (IGF-IR) and HGF-SF (c-met) receptor expression showed significantly higher expression of both receptors in normal liver compared with an HCC specimen. Using cultured HCC cells from this model, we next showed that treatment with IGF-I led to significant increases in mitogen-activated protein kinase (MAPK) activity. Furthermore, we observed significant time-dependent increases in the expression of the c-fos and c-jun proto-oncogenes after addition of IGF-I (n = 5 per group, P <.05). Despite activation of a MAPK pathway and increased proto-oncogene expression, IGF-I failed to significantly affect cell mitogenesis. In contrast, HGF significantly inhibited cell mitogenesis in HCC lines (68.4% +/- 9.4% vs. control, n = 4, P <.05). Pretreatment of HCC cells with IGF-I (60 minutes) led to significant HGF-SF stimulation of total cell mitogenesis dependent on both IGF-I and HGF-SF dose (194% +/- 8% increase vs. control, n = 4, P <.05). In conclusion, tumor burden is important in altering intrahepatic growth factor synthesis. Signal cooperation between multiple cytokine pathways is an important factor in the progression of HCC.
authors.affiliation: Department of Surgery, University of Rochester Medical Center, NY, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Price
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kovach
authors.forename: Timothy
authors.initials: T
authors.lastname: Johnson
authors.forename: Leonidas G
authors.initials: LG
authors.lastname: Koniaris
authors.forename: Paul A
authors.initials: PA
authors.lastname: Cahill
authors.forename: James V
authors.initials: JV
authors.lastname: Sitzmann
authors.forename: Iain H
authors.initials: IH
authors.lastname: McKillop
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000503:physiopathology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000235:genetics* / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D008113:Liver Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008934:Mitogens / Q000097:blood / Q000235:genetics* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011912:Rats, Inbred ACI; D017526:Receptor, IGF Type 1 / Q000235:genetics
chemical_list: D008934:Mitogens; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D019859:Proto-Oncogene Proteins c-met; D017526:Receptor, IGF Type 1; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases