GH administration patterns differently regulate epidermal growth factor signaling

Abstract

Current GH administration protocols imply frequent s.c. injections, resulting in suboptimal compliance. Therefore, there is interest in developing delivery systems for sustained release of the hormone. However, GH has different actions depending on its continuous or pulsatile plasma concentration pattern. GH levels and circulating concentration patterns could be involved in the regulation of epidermal growth factor receptor (EGFR) expression in liver. Aberrant expression of this receptor and/or its hyperactivation has been associated with the pathogenesis of different types of carcinoma. Considering that one of the adverse effects associated with GH overexpression and chronic use of GH is the increased incidence of malignancies, the aim of this study was to analyze the effects of GH plasma concentration patterns on EGFR expression and signaling in livers of mice. For this purpose, GH was administered by s.c. daily injections to produce an intermittent plasma pattern or by osmotic pumps to provoke a continuously elevated GH concentration. Intermittent injections of GH induced upregulation of liver EGFR content, augmented the response to EGF, and the induction of proteins involved in promotion of cell proliferation in female mice. In contrast, continuous GH delivery in male mice was associated with diminished EGFR in liver and decreased EGF-induced signaling and expression of early genes. The results indicate that sustained delivery systems that allow continuous GH plasma patterns would be beneficial in terms of treatment safety with regard to the actions of GH on EGFR signaling and its promitogenic activity.

Attenuation of epidermal growth factor (EGF) signaling by growth hormone (GH)

“…GH-overexpressing transgenic mice showed increased EGFR hepatic levels (González et al 2010) but reduced or similar EGF induction of c-MYC, c-JUN, c-FOS and CYCLINs with respect to normal siblings. These results are different from those described for normal mice receiving intermittent injections of GH during a short period (Díaz et al 2014). In that case, the treatment induced a significant upregulation of the receptor and, concomitantly, an increased expression of early genes involved in cell cycle control.…”

“…In that case, the treatment induced a significant upregulation of the receptor and, concomitantly, an increased expression of early genes involved in cell cycle control. The difference between both models is the nature of GH influence over EGF signaling pathways; chronic and continuous circulating GH levels caused an upregulation of EGFR liver content but a desensitization of EGF signaling (González et al 2010, Díaz et al 2012, whereas short-term treatment with intermittent injections of EGF also produced an increase in EGFR protein content but upregulated EGF signaling (Díaz et al 2014). Therefore, the next goal was to elucidate possible mechanisms involved in the attenuation of EGF signal in the liver of transgenic mice.…”

“…injection of recombinant human EGF at 2 mg/kg BW in 0.9% w/v NaCl. Animals were killed by cervical dislocation under isoflurane anesthesia 2.5, 5, 10 and 15 min after administration of EGF (Díaz et al 2012) to study the phosphorylation of EGF signaling mediators or after 1 h or 4 h to study the expression of early genes and Cyclins involved in the induction of cell cycle progression (Díaz et al 2014). Non-stimulated mice were used to evaluate basal conditions (considered as time 0).…”

“…qPCR assays were performed using oligonucleotide primers for CyclinD1 (Ccnd1) (5′-GCGAAGTGGAGACCATCCG and 5′-GGTCTC CTCCGTCTTGAGC), CyclinE (Ccne1) (5′-GGCGGACACAGCTTCGGGTC and 5′-TGGGTCTTGCAAAAACACGGCCA), and Cyclophilin A (5′-GCGTCTCCTTCGAGCTGTT and 5′-AAGTCACCACCCTGGCAC). Cyclophilin A was chosen as the housekeeping gene (Díaz et al 2014). Reaction data were collected and analyzed using complementary computer software (Sequence Detection Software, Applied Biosystems, version 1.3).…”

Not So Giants: Mice Lacking Both Somatostatin and Cortistatin Have High GH Levels but Show No Changes in Growth Rate or IGF-1 Levels

“…Further support to the idea that the liver of our double-KO mice model had partial resistance to GH actions was obtained by measuring hepatic egf-r expression, a molecular marker reported to be highly sensitive to GH levels and to the pattern of GH delivery, and to be associated to liver resistance. In fact, Diaz et al (23) recently reported that continuous GH delivery in male mice suppresses egf-r, which was associated with a loss of hepatic GH responsiveness as observed in models with low GH levels [ie, ob/ob (24)]. Accordingly, double-SST/ CORT-KO mice with elevated GH levels in a feminized pattern displayed a markedly reduced hepatic egf-r expression, which would likely be accompanied by reduced hepatic GH responsiveness/partial GH resistance that may explain the lack of an IGF-1 rise in a model with high GH levels.…”