Overexpressed growth hormone (GH) synergistically promotes carcinogen-initiated liver tumour growth by promoting cellular proliferation in emerging hepatocellular neoplasms in female and male GH-transgenic mice

During the maturation of the cardiac myocyte, a transition occurs from hyperplastic to hypertrophic growth. The factors that control this transition in the developing heart are unknown. Proto-oncogenes such as c-myc have been implicated in the regulation of cellular proliferation and differentiation, and in the heart the switch from myocyte proliferation to terminal differentiation is synchronous with a decrease in c-myc mRNA abundance. To determine whether c-myc can influence myocyte proliferation or differentiation, we examined the in vivo effect of increasing c-myc expression during embryogenesis and of preventing the decrease in c-myc mRNA expression that normally occurs during cardiac development. The model system used was a strain of transgenic mice exhibiting constitutive expression of c-myc mRNA in cardiac myocytes throughout development. In these transgenic mice, increased c-myc mRNA expression was found to be associated with both atrial and ventricular enlargement. This increase in cardiac mass was secondary to myocyte hyperplasia, with the transgenic hearts containing more than twice as many myocytes as did nontransgenic hearts. The results suggest that in the transgenic animals there is additional hyperplastic growth during fetal development. However, this additional proliferative growth is not reflected in abnormal myocyte maturation, as assessed by the expression of the cardiac and skeletal isoforms of alpha-actin. The results of this study indicate that constitutive expression of c-myc mRNA in the heart during development results in enhanced hyperplastic growth and suggest a regulatory role for this proto-oncogene in cardiac myogenesis.

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Opposing Roles of Peroxisome Proliferator-activated Receptor α and Growth Hormone in the Regulation of CYP4A11 Expression in a Transgenic Mouse Model

Journal of Biological Chemistry ◽

10.1074/jbc.m902074200 ◽

2009 ◽

Vol 284 (24) ◽

pp. 16541-16552 ◽

Cited By ~ 23

Author(s):

Üzen Savas ◽

Daniel E. W. Machemer ◽

Mei-Hui Hsu ◽

Pryce Gaynor ◽

Jerome M. Lasker ◽

...

Keyword(s):

Gene Expression ◽

Growth Hormone ◽

Transgenic Mice ◽

Hormone Secretion ◽

Growth Hormone Secretion ◽

Peroxisome Proliferator ◽

Sexually Dimorphic ◽

Peroxisome Proliferator Activated Receptor ◽

Liver And Kidney

CYP4A11 transgenic mice (CYP4A11 Tg) were generated to examine in vivo regulation of the human CYP4A11 gene. Expression of CYP4A11 in mice yields liver and kidney P450 4A11 levels similar to those found in the corresponding human tissues and leads to an increased microsomal capacity for ω-hydroxylation of lauric acid. Fasted CYP4A11 Tg mice exhibit 2–3-fold increases in hepatic CYP4A11 mRNA and protein, and this response is absent in peroxisome proliferator-activated receptor α (PPARα) null mice. Dietary administration of either of the PPARα agonists, fenofibrate or clofibric acid, increases hepatic and renal CYP4A11 levels by 2–3-fold, and these responses were also abrogated in PPARα null mice. Basal liver CYP4A11 levels are reduced differentially in PPARα−/− females (>95%) and males (<50%) compared with PPARα−/+ mice. Quantitative and temporal differences in growth hormone secretion are known to alter hepatic lipid metabolism and to underlie sexually dimorphic gene expression, respectively. Continuous infusion of low levels of growth hormone reduced CYP4A11 expression by 50% in PPARα-proficient male and female transgenic mice. A larger decrease was observed for the expression of CYP4A11 in PPARα−/− CYP4A11 Tg male mice to levels similar to that of female PPARα-deficient mice. These results suggest that PPARα contributes to the maintenance of basal CYP4A11 expression and mediates CYP4A11 induction in response to fibrates or fasting. In contrast, increased exposure to growth hormone down-regulates CYP4A11 expression in liver.

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Abstract 1414: Pim-1 Stimulates Cardiac Progenitor Cell Proliferation And Asymmetric Division

Circulation ◽

10.1161/circ.118.suppl_18.s_321-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Christopher T Cottage ◽

Savilla Tuck ◽

Kimberlee Fischer ◽

Natalie Gude ◽

John Muraski ◽

...

Keyword(s):

Transgenic Mice ◽

Cell Fate ◽

Cellular Proliferation ◽

Gene Promoter ◽

Asymmetric Division ◽

Postnatal Growth ◽

Chain Gene ◽

Ki 67 ◽

Population Number ◽

Mechanistic Basis

Cardiac progenitor cells (CPCs) blunt cardiomyopathic damage and increase survival following adoptive transfer into hearts subjected to myocardial infarction (MI), but the initial survival, persistence, and long term engraftment of the donated cell population remains problematic. Previous studies from our group have demonstrated that transgenes driven by the α -myosin heavy chain gene promoter are expressed in the CPC population allowing for enhanced proliferation and survival. This study details a genetic engineering strategy to augment the salutary effects of CPCs through the use of a serine/threonine kinase named Pim-1 that promotes cellular proliferation and survival. Transgenic mice created with cardiac-specific Pim-1 overexpression (Pim-wt) exhibit enhanced Pim-1 activity in both cardiomyocytes and CPCs, both of which show increased proliferative activity assessed using BrdU or Ki-67 markers relative to non-transgenic (NTG) controls. However, CPC population number was not increased in the Pim-wt hearts during normal postnatal growth or after infarction challenge, suggesting that Pim-1 expression promotes asymmetric division resulting in maintenance of the CPC pool as well as expansion of the cardiomyocyte population. Localization and quantitation of cell fate determinants Numb and α -adaptin by confocal microscopy were employed to assess levels of asymmetric division in the CPC population. Polarization of Numb in mitotic phospho-histone positive cells demonstrates asymmetric division in 65% of the CPC population in hearts of Pim-wt mice versus 26% in NTG hearts after infarction challenge. Similarly, Pim-wt hearts had fewer cells with uniform α -adaptin staining indicative of symmetrically dividing CPCs, with in 36% of the CPCs versus vs. 73% in NTG sections. These findings define a mechanistic basis for enhanced myocardial regeneration in transgenic mice overexpressing Pim-1 kinase in the myocardial lineage cells.

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Cytostatics for acromegaly

Acta Endocrinologica ◽

10.1530/acta.0.1160347 ◽

1987 ◽

Vol 116 (3) ◽

pp. 347-349 ◽

Cited By ~ 9

Author(s):

A. A. Kasperlik-Zaluska ◽

J. Wislawski ◽

J. Kaniewska ◽

J. Zborzil ◽

E. Frankiewicz ◽

...

Keyword(s):

Growth Hormone ◽

Visual Field ◽

Ct Scan ◽

Tumour Growth ◽

Pituitary Tumour ◽

Hormone Concentration ◽

Serum Growth Hormone ◽

X Ray ◽

Transcranial Approach ◽

Symptoms And Signs

Abstract. A 21-year-old woman suffering from acromegaly was treated with transsphenoidal subtotal hypophysectomy (microscopy: acidophilic adenoma), followed by x-ray and bromocriptine therapy. Seven years later she was re-operated because of a partial bitemporal loss of vision, intracranial hypertension, and regrowth of the pituitary tumour seen on CT-scan. A large part of the invasive suprasellar tumour was then removed by transcranial approach. The neurosurgery was followed by cobalt radiotherapy and bromocriptine administration. Two years later, symptoms and signs of tumour growth reappeared. Administration of cytostatics, such as doxorubicin (Adriamycin®) and lomustine (Belustine®), resulted in distinct clinical improvement associated with a seven-fold decrease in the serum growth hormone concentration. The visual field became normal and the intracranial mass on a CT scan decreased markedly. As a result the patient was able to resume work.

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Growth hormone upregulates the pro-tumorigenic galectin 1 in mouse liver

Endocrine Connections ◽

10.1530/ec-19-0292 ◽

2019 ◽

Vol 8 (8) ◽

pp. 1108-1117 ◽

Cited By ~ 2

Author(s):

María L Bacigalupo ◽

Verónica G Piazza ◽

Nadia S Cicconi ◽

Pablo Carabias ◽

Andrzej Bartke ◽

...

Keyword(s):

Growth Hormone ◽

Transgenic Mice ◽

Mouse Liver ◽

Liver Tumors ◽

Tumor Development ◽

Hepatic Cancer ◽

Liver Pathology ◽

Liver Carcinogenesis ◽

Short Period ◽

Hcc Cells

Transgenic mice overexpressing growth hormone (GH) spontaneously develop liver tumors, including hepatocellular carcinoma (HCC), within a year. The preneoplastic liver pathology in these mice recapitulates that observed in humans at high risk of developing hepatic cancer. Although increased expression of galectin 1 (GAL1) in liver tissue is associated with HCC aggressiveness, a link between this glycan-binding protein and hormone-related tumor development has not yet been explored. In this study, we investigated GAL1 expression during liver tumor progression in mice continuously exposed to high levels of GH. GAL1 expression was determined by Western blotting, RT-qPCR and immunohistochemistry in the liver of transgenic mice overexpressing GH. Animals of representative ages at different stages of liver pathology were studied. GAL1 expression was upregulated in the liver of GH-transgenic mice. This effect was observed at early ages, when animals displayed no signs of liver disease or minimal histopathological alterations and was also detected in young adults with preneoplastic liver pathology. Remarkably, GAL1 upregulation was sustained during aging and its expression was particularly enhanced in liver tumors. GH also induced hepatic GAL1 expression in mice that were treated with this hormone for a short period. Moreover, GH triggered a rapid increment in GAL1 protein expression in human HCC cells, denoting a direct effect of the hormone on hepatocytes. Therefore, our results indicate that GH upregulates GAL1 expression in mouse liver, which may have critical implications in tumorigenesis. These findings suggest that this lectin could be implicated in hormone-driven liver carcinogenesis.

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Effect of recombinant human growth hormone on acute and chronic human immunodeficiency virus infection in vitro

Blood ◽

10.1182/blood.v79.2.467.bloodjournal792467 ◽

1992 ◽

Vol 79 (2) ◽

pp. 467-472

Author(s):

J Laurence ◽

B Grimison ◽

A Gonenne

Keyword(s):

Growth Hormone ◽

Human Immunodeficiency Virus ◽

Viral Replication ◽

Human Growth Hormone ◽

Cellular Proliferation ◽

Recombinant Human Growth Hormone ◽

Human Growth ◽

Immunodeficiency Virus ◽

Hiv 1

Growth hormone (somatotropin) is a potent anabolic protein currently being evaluated clinically in cachexia associated with malignancy and human immunodeficiency virus (HIV) disease. Growth hormone can also lead to enhancement of lectin-mediated cellular proliferation, macrophage activation, and cytokine induction, events linked to induction of latent HIV in vitro. We thus explored the ability of recombinant human growth hormone (rhGH) to affect viral replication in acute and chronic HIV infection, and to alter transcription at the HIV- 1 long terminal repeat (LTR). A clone of promonocytic cells, chronically infected with HIV-1 and susceptible to viral induction by a variety of cytokines and protein kinase C activators, was unperturbed by rhGH used over broad concentrations (10 to 500 ng/mL) and time intervals. This unresponsiveness paralleled the lack of effect of rhGH on HIV-associated trans-activation in both monocytic and CD4+ T-cell lines. In contrast, rhGH enhanced viral replication in acutely infected peripheral blood mononuclear cells (PBMC) by twofold to 20-fold, albeit having no adverse effect on the antiviral efficacy of zidovudine (AZT). Augmentation of HIV growth correlated with stimulation of cellular DNA synthetic responses and an increase in tumor necrosis factor-alpha (TNF- alpha) secretion. These data are discussed in the context of ongoing clinical trials of rhGH in HIV-seropositive individuals with wasting syndromes.

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