title: 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.
authors: Department of Biological Chemistry-IQUIFIB (CONICET), School of Pharmacy and Biochemistry, University of Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina. jmiquet@qb.ffyb.uba.ar
authors: Johanna G
authors: JG
authors: Miquet
authors: Thomas
authors: T
authors: Freund
authors: Carolina S
authors: CS
authors: Martinez
authors: Lorena
authors: L
authors: González
authors: María E
authors: ME
authors: Díaz
authors: Giannina P
authors: GP
authors: Micucci
authors: Elsa
authors: E
authors: Zotta
authors: Ravneet K
authors: RK
authors: Boparai
authors: Andrzej
authors: A
authors: Bartke
authors: Daniel
authors: D
authors: Turyn
authors: Ana I
authors: AI
authors: Sotelo
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D019938:Cyclin D1 / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D050791:STAT Transcription Factors; D019938:Cyclin D1; D013006:Growth Hormone; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: GSK3β; NFκB; c-fos; c-jun; c-myc; cyclin D1; cyclin E; growth hormone; liver; β-catenin