Growth hormone (GH) treatment effects on cellular proliferation and signaling pathways related to tumorogenesis processes in the liver of mice.

PIAZZA VG ; CICCONI NS ; MIQUET JG; SOTELO AI

Buenos Aires

Congreso; IV International Congress in Translational Medicine; 2018

Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires

Prolonged exposure togrowth hormone (GH) in mice is associated with hepatomegaly, due to hypertrophyand hyperplasia of hepatocytes, and old GH-overexpressing transgenic micefrequently develop liver tumors. Young adult transgenic mice presentpreneoplastic pathology in the liver and exhibit alterations in signalingpathways involved in cell growth and proliferation in that tissue. These changes could be a direct effect of prolonged GHaction or secondary to the pathological context produced by hormone excess.Consequently, the aim of this work was to assess if lower levels of GHadministered for a limited period would also induce any of these alterations. For that purpose, mice were treated with 6 µg/g of bodyweight of GH per day by osmotic pumps between 3- and 8-weeks of age and liverswere removed at the end of treatment.To evaluatehepatocellular proliferation, the expression of proliferating cell nuclearantigen (PCNA) was determined in liver sections. In comparison to controls,GH-treated males exhibited an increased percentage of PCNA positive nuclei,whereas non-significant differences were observed in females. As a consequenceof GH-treatment, both male and female mice exhibited higher hepatic mRNA levelsof GH receptor than controls, together with an increased gene expression of negativemodulators of GH-signaling (CIS and SOCS2). Signaling pathways known to beinvolved in cell growth and proliferation processes were also evaluated. GH-exposedanimals displayed an increase in STAT3 activation in comparison to controls. Akt and ERK1/2 protein content was also higher in treated mice, only in males, although it did notresult in an exacerbated activation of these mediators. When the expression of cellcycle regulators was analyzed, GH-treated males exhibited higher geneexpression of cyclin D1 than control animals, with no changes in c-Myc, c-Fosand c-Jun expression. On the other hand, females exposed to GH displayedincreased levels of c-Myc mRNA, but not of any of the other proto-oncogenesanalyzed, in comparison to non-treated mice. Consequently,limited exposure to sustained low levels of GH is associated with morphological and molecular changes in the liver that could provide a pro-tumorigenic environment,especially in males.