Hepatocellular alterations and dysregulation of oncogenic pathways in the liver of transgenic mice overexpressing growth hormone

Abstract

Growth hormone (GH) overexpression throughout life in transgenic mice is associated with the development of liver tumors at old ages. The preneoplastic pathology observed in the liver of young adult GH-overexpressing mice is similar to that present in humans at high risk of hepatic cancer. To elucidate the molecular pathogenesis underlying the pro-oncogenic liver pathology induced by prolonged exposure to elevated GH levels, the activation and expression of several components of signal transduction pathways that have been implicated in hepatocellular carcinogenesis were evaluated in the liver of young adult GH-transgenic mice. In addition, males and females were analyzed in parallel in order to evaluate sexual dimorphism. Transgenic mice from both sexes exhibited hepatocyte hypertrophy with enlarged nuclear size and exacerbated hepatocellular proliferation, which were higher in males. Dysregulation of several oncogenic pathways was observed in the liver of GH-overexpressing transgenic mice. Many signaling mediators and effectors were upregulated in transgenic mice compared with normal controls, including Akt2, NFκB, GSK3β, β-catenin, cyclin D1, cyclin E, c-myc, c-jun and c-fos. The molecular alterations described did not exhibit sexual dimorphism in transgenic mice except for higher gene expression and nuclear localization of cyclin D1 in males. We conclude that prolonged exposure to GH induces in the liver alterations in signaling pathways involved in cell growth, proliferation and survival that resemble those found in many human tumors.

GH administration patterns differently regulate epidermal growth factor signaling

“…As previously discussed for expression of MUPs, EGFR was not significantly induced in male mice that received injections of GH because EGFR liver content is already high due to the endogenous secretion pattern of the hormone. In contrast, a reduction in EGFR levels was not evident in livers of female mice after continuous GH treatment, probably because the receptor content is already low compared with male mice (Miquet et al 2013).…”

“…However, studies concerning the effects of plasma GH pattern on EGFR expression are still controversial. In rodents, EGFR expression is higher in males than in females as evidenced by specific binding of labeled EGF to purified liver membranes, determination of EGFR mRNA, and immunoblotting from solubilized liver (Ekberg et al 1989, Johansson et al 1989, Miquet et al 2013. Furthermore, in hypophysectomized rats of both sexes, intermittent GH treatment enhanced hepatic Egfr mRNA concentrations compared with levels for normal male rats, while continuous GH administration was less effective or did not have any effects at all (Ekberg et al 1989, Kashimata et al 1989.…”

Growth hormone is permissive for neoplastic colon growth

“…The latter are believed to be a consequence of the direct effect of GH on the liver rather than mediated by IGF1, as transgenic mice overexpressing IGF1 do not exhibit similar liver pathology (22,23). Furthermore, acromegaly patients with excess systemic GH elaborated by a GH secreting pituitary tumor have increased prevalence of colon polyps (24)(25)(26) as well as increased colon length with prominent mucosal folds and overgrowth (27), and also exhibit fourfold increased rates of colon adenocarcinoma (28)(29)(30)(31).…”

The growth hormone receptor mediated oncogenesis

“…A decrease in EGFR activation has been previously reported in GHR KO (Zerrad-Saadi et al, 2011). In addition, the downstream signalling molecule to IGF-1R and IR, Akt2 was reduced in GHR KO and K4 mice while its level has been reported to be upregulated in GHtg mice that have various hepatocellular abnormalities (Miquet et al, 2013). GHR KO males and females have increased transcript expression of cdkn1a that encodes for p21, inhibitory regulator of cell cycle progression.…”

“…Increased inflammation, hepatocellular carcinoma and premature death have been reported in two different models of GHtg mice (Wanke et al, 1991;Friedbichler et al, 2011). Dysregulation of several oncogenic pathways and signalling mediators were reported in the liver of GHtg mice of both genders as compared with normal controls, including Akt2, NF-κB, GSK3β, β-catenin, cyclin D1, cyclin E, c-myc, c-jun and c-fos (Miquet et al, 2013). Also, acromegalics have been reported to have a higher incidence of colon and thyroid cancers (Chhabra et al, 2011) while other increased tumour incidences have not been confirmed due to small sample size.…”