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

The use of growth hormone has risen in the last years. Apart from its interactions in growth and metabolism, its use has been approved in different clinical conditions which do not necessarily implicate the lack of GH. Furthermore, GH is used to prevent attributes of aging and to gain better athletic condition, without being approved for these cases. In this context, it should be clear that the use of GH is not free from side effects. A serious side effect of the use or the abuse of GH could be the development of tumors. The excess of GH is associated with the development of liver tumors in mice. Possible mechanisms for GH promoting this type of cancer imply its effect on cellular proliferation and the modulation of signaling components involved in a large range of processes i.e. inflammation. The objective of this work was to elucidate the molecular pathogenesis and signal transduction pathways underlying the pro-oncogenic liver pathology induced by prolonged exposure to elevated GH level. The sexual dimorphic pulsatile GH secretion and the higher incidence of HCC in males, both in humans and in mice (Rogers et al., 2007; Ruggiere et al., 2010), bundled the focus in this work on sexual dimorphism within molecular alterations in preneoplastic lesions in young adult GH-transgenic mice compared to their normal controls. The fact that old GH-transgenic mice, more than 1 year of age, frequently develop liver tumors, set the second focus in this work on the deviation in hepatocellular molecular alterations between tumoral and non-tumoral lesions to reach understanding in the ultimate step from preneoplastic to neoplastic lesion. Activation and expression of several downstream components, including NF-κB, GSK3-β, β-catenin, c-Myc, c-Jun, c-Fos, cyclin D1 and cyclin E, of signal transduction pathways that have been implicated in hepatocellular carcinogenesis, like PI3K/Akt and STATs were evaluated in the liver of young adult, 9 weeks old, male and female as well as in old female GH-transgenic mice and their normal controls, to assess its possible association with the liver pathology observed in these animals. Referring to sexual dimorphism in this work, young adult, normal male mice depict higher hepatocyte cellular and nuclear size, but cell proliferation was not increased. In addition molecular signaling mediators like STAT5, Akt and GSK3-β showed higher phosphorylated activation content for young adult male mice in the normal group. Young adult GH-overexpressing transgenic mice from both sexes exhibit hepatomegaly, hepatocyte hypertrophy with enlarged nuclear size and exacerbated hepatocellular proliferation compared to their normal controls. Long-lasting elevated expression of c-myc, c-jun and c-fos is observed in the liver of transgenic mice overexpressing GH from young adult to old animals, underlining the reported important role of these protooncogenes in the pre neoplastic pathology observed in this model.