GH modulates hepatic epidermal growth factor signaling in the mouse

Abstract

Epidermal growth factor (EGF) is a key regulator of cell survival and proliferation involved in the pathogenesis and progression of different types of cancer. The EGF receptor (EGFR) is activated by binding of the specific ligand but also by transactivation triggered by different growth factors including GH. Chronically, elevated GH levels have been associated with the progression of hepatocellular carcinoma. Considering EGF and GH involvement in cell proliferation and their signaling crosstalk, the objective of the present study was to analyze GH modulatory effects on EGF signaling in liver. For this purpose, GH receptor-knockout (GHR-KO) and GH-overexpressing transgenic mice were used. EGFR content was significantly decreased in GHR-KO mice. Consequently, EGF–induced phosphorylation of EGFR, AKT, ERK1/2, STAT3, and STAT5 was significantly decreased in these mice. In contrast, EGFR content as well as its basal tyrosine phosphorylation was increased in transgenic mice overexpressing GH. However, EGF stimulation caused similar levels of EGFR, AKT, and ERK1/2 phosphorylation in normal and transgenic mice, while EGF induction of STAT3 and STAT5 phosphorylation was inhibited in the transgenic mice. Desensitization of the STATs was related to decreased association of these proteins to the EGFR and increased association between STAT5 and the tyrosine phosphatase SH2-containing phosphatase-2. While GHR knockout is associated with diminished expression of the EGFR and a concomitant decrease in EGF signaling, GH overexpression results in EGFR overexpression with different effects depending on the signaling pathway analyzed: AKT and ERK1/2 pathways are induced by EGF, while STAT3 and STAT5 activation is heterologously desensitized.

Association of serum levels of epidermal growth factor with disease severity in patients with unresectable hepatocellular carcinoma

“…[8] Epidermal growth factor (EGF), another key regulator of cell survival and proliferation, is another biomarker identified in the pathogenesis and progression of different types of cancer. [9] During 1980s, several reports described the overexpression of EGF and EGF receptor (EGFR) in a variety of epithelial tumors, which may have a critical role in the etiology of human cancers. [10,11] EGF is also speculated to enhance the transformation of fibroblasts to fibrosarcomas by inducing the development of HCC in transgenic mice.…”

Growth hormone (GH) modulation of Epidermal growth factor (EGF) signalling in human mammary epithelial cells

“…Crosstalk between GH and EGF signalling pathways has been described; moreover, EGFR expression has been demonstrated to be regulated by GH (Jansson et al, 1988;Johansson et al, 1989;Miquet et al, 2008;González et al, 2010). GH caused tyrosine phosphorylation of the EGFR and subsequent MAPK signalling in mice livers and cell culture (Yamauchi et al, 1997).…”

“…GH was first described to induce Tyr1068 phosphorylation at EGFR in vitro and in vivo (Yamauchi et al, 1997, exogenous GH administration this expression deficit can be reversed (Jansson et al, 1988;Johansson et al, 1989). In transgenic mice overexpressing GH, EGFR levels are increased, whereas GH receptor-KO mice have diminished protein content (Miquet et al, 2008;González et al, 2010). In mice lacking the GH-receptor, consequently to less EGFR-expression, EGF-stimulated AKT, ERK1/2, STAT-3 and STAT-5 phosphorylation is diminished compared to normal mice (González et al, 2010).…”

“…In transgenic mice overexpressing GH, EGFR levels are increased, whereas GH receptor-KO mice have diminished protein content (Miquet et al, 2008;González et al, 2010). In mice lacking the GH-receptor, consequently to less EGFR-expression, EGF-stimulated AKT, ERK1/2, STAT-3 and STAT-5 phosphorylation is diminished compared to normal mice (González et al, 2010).…”

“…In hypophysectomized or GH-deficient mutant mice, EGFR expression is diminished in liver tissue (Jannson et al, 1988;González et al, 2010) and GH-treatment reverses this downregulation of receptors (Jannson et al, 1988). Moreover, EGFR expression is increased in the liver of transgenic mice overexpresing GH (Miquet et al, 2008;González et al, 2010) EGF-induced phosphorylation of EGFR at its tyrosine residues results in downstream signalling cascades as the mitogen activated protein kinase Ras/Raf/MEK/ERK (p44/p42 MAPK), the PI3K/AKT and the STAT-pathways (Jorrisen et al, 2003;Schulze et al, 2005;Normanno et.al., 2006). These pathways are involved in cell survival and growth.…”