Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma

Julie A. Price, Stephen J. Kovach, Timothy Johnson, Leonidas Koniaris, Paul A. Cahill, James V. Sitzmann, Iain H. McKillop

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1089-1097
Number of pages9
JournalHepatology
Volume36
Issue number5 II
DOIs
StatePublished - Nov 1 2002
Externally publishedYes

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Hepatocyte Growth Factor
Insulin-Like Growth Factor I
Hepatocellular Carcinoma
Mitogen-Activated Protein Kinases
Liver
Intercellular Signaling Peptides and Proteins
jun Genes
IGF Type 1 Receptor
Proto-Oncogenes
Growth
Tumor Burden
Mitogens
Cell Differentiation
Neoplasms
Cytokines
Messenger RNA

ASJC Scopus subject areas

  • Hepatology

Cite this

Price, J. A., Kovach, S. J., Johnson, T., Koniaris, L., Cahill, P. A., Sitzmann, J. V., & McKillop, I. H. (2002). Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma. Hepatology, 36(5 II), 1089-1097. https://doi.org/10.1053/jhep.2002.36158

Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma. / Price, Julie A.; Kovach, Stephen J.; Johnson, Timothy; Koniaris, Leonidas; Cahill, Paul A.; Sitzmann, James V.; McKillop, Iain H.

In: Hepatology, Vol. 36, No. 5 II, 01.11.2002, p. 1089-1097.

Research output: Contribution to journalArticle

Price, JA, Kovach, SJ, Johnson, T, Koniaris, L, Cahill, PA, Sitzmann, JV & McKillop, IH 2002, 'Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma', Hepatology, vol. 36, no. 5 II, pp. 1089-1097. https://doi.org/10.1053/jhep.2002.36158
Price, Julie A. ; Kovach, Stephen J. ; Johnson, Timothy ; Koniaris, Leonidas ; Cahill, Paul A. ; Sitzmann, James V. ; McKillop, Iain H. / Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma. In: Hepatology. 2002 ; Vol. 36, No. 5 II. pp. 1089-1097.
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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.",
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