Search Results (15)

Individuals with Laron syndrome, a rare condition characterized by congenital insulin-like growth factor 1 (IGF-1) deficiency, display a remarkably low incidence of cancer, suggesting the existence of protective mechanisms linking reduced IGF-1 signaling to decreased cancer susceptibility. Consistent with this observation, IGF-1 is a recognized promoter of prostate cancer (PCa) progression, although the underlying mechanisms remain incompletely understood. Methylglyoxal (MG)-derived glycative stress, reflected by the accumulation of MG-derived hydroimidazolone 1 (MG-H1), has been implicated in PCa progression but has never been investigated in Laron syndrome. We found that liver tissues from Laron mice exhibited lower MG-H1 levels, suggesting reduced MG-derived glycative stress associated with low IGF-1 signaling. These findings prompted us to investigate whether MG-derived glycative stress contributes to IGF-1-driven PCa progression. Compared with the less aggressive LNCaP cells, PC3 cells displayed higher basal IGF-1 and MG-H1 levels, consistent with a potential association between IGF-1 and MG-derived glycative stress in PCa progression. Moreover, IGF-1 stimulation of LNCaP cells increased MG-H1 accumulation, proliferation, colony formation, invasiveness, and gene expression of matrix metalloproteinase (MMP)-1, MMP-7, MMP-9, receptor for advanced glycation end-products (RAGE), and Osteopontin (OPN), all of which were markedly attenuated by the MG scavenger aminoguanidine (AG). Collectively, these findings support a potential contribution of MG-derived glycative stress to IGF-1-driven PCa progression. Full article

Background: In the literature, the occurrence of menarche, the index of female sexual maturation, is related to chronological age (CA), but in conditions of abnormal growth it was proposed that determination of bone age (BA) was a better index of pubertal maturation than CA. Aim: To compare CA with BA at menarche in girls with Laron Syndrome (LS), a model of genetic IGF-I deficiency, which causes severe dwarfism and delayed puberty. Subjects: Data were retrieved retrospectively from our medical records. Nine untreated and four IGF-I-treated girls with LS were included in the study. Eleven GH-treated girls with congenital isolated GH deficiency (cIGHD) served as comparison. Results: The mean BA at menarche of untreated LS patients (13.4 y) was 0.7 y less than the CA (14.1 y), and the mean BA of IGF-I-treated girls (13.7 y) was 1.2 y less than the CA (14.9 y). Body height and weight did not influence the age at menarche. Conclusion: In girls with LS, the determination of BA seems a more useful index of female pubertal maturation than CA. Full article

Background: Laron Syndrome (LS) is a rare hereditary form of dwarfism occurring, with few exceptions, in Jewish, Muslim, and Asian populations or their descendants spread over all continents. It is caused by deletions or mutations in the GH-Receptor gene, resulting in high serum levels of a structurally and biologically normal, but inactive GH and low-to-undetectable IGF-I. Aim: To summarize the disabilities and handicaps observed in patients with LS, from infancy through adult age. Results: Diagnosing, treating and following a cohort of 76 patients with LS (in many cases from infancy into adult age) enabled our department to study not only their growth and social achievements, but also the difficulties these patients encounter in life. The longstanding IGF-I deficiency caused somatic and biochemical changes which led to disabilities starting in infancy and becoming more severe with advancing age. The most serious symptoms LS patients have are dwarfism, progressive obesity, diabetes, fatty liver, cardiovascular disease, and neurological and orthopedic problems, leading to difficulties in vocational training, occupation, and social life, all lowering the Quality of Life (QoL) of these patients. Conclusions: Early initiation of IGF-I replacement treatment in patients with Laron Syndrome prevents and reverses some of the symptoms associated with longstanding IGF-I deficiency. Full article

Richard Peto’s paradox, first described in 1975 from an epidemiological perspective, established an inverse correlation between the probability of developing cancer in multicellular organisms and the number of cells. Larger animals exhibit fewer tumors compared to smaller ones, though exceptions exist. Mice are more susceptible to cancer than humans, while elephants and whales demonstrate significantly lower cancer prevalence rates than humans. How nature and evolution have addressed the issue of cancer in the animal kingdom remains largely unexplored. In the field of medicine, much attention has been devoted to cancer-predisposing genes, as they offer avenues for intervention, including blocking, downregulating, early diagnosis, and targeted treatment. Predisposing genes also tend to manifest clinically earlier and more aggressively, making them easier to identify. However, despite significant strides in modern medicine, the role of protective genes lags behind. Identifying genes with a mild predisposing effect poses a significant challenge. Consequently, comprehending the protective function conferred by genes becomes even more elusive, and their very existence is subject to questioning. While the role of variable expressivity and penetrance defects of the same variant in a family is well-documented for many hereditary cancer syndromes, attempts to delineate the function of protective/modifier alleles have been restricted to a few instances. In this review, we endeavor to elucidate the role of protective genes observed in the animal kingdom, within certain genetic syndromes that appear to act as cancer-resistant/repressor alleles. Additionally, we explore the role of protective alleles in conditions predisposing to cancer. The ultimate goal is to discern why individuals, like Winston Churchill, managed to live up to 91 years of age, despite engaging in minimal physical activity, consuming large quantities of alcohol daily, and not abstaining from smoking. Full article

Laron syndrome (LS) is a rare genetic disorder characterized by low levels of insulin-like growth factor 1 (IGF1) and high levels of growth hormone (GH) due to mutations in the growth hormone receptor gene (GHR). A GHR-knockout (GHR-KO) pig was developed as a model for LS, which displays many of the same features as humans with LS-like transient juvenile hypoglycemia. This study aimed to investigate the effects of impaired GHR signaling on immune functions and immunometabolism in GHR-KO pigs. GHR are located on various cell types of the immune system. Therefore, we investigated lymphocyte subsets, proliferative and respiratory capacity of peripheral blood mononuclear cells (PBMCs), proteome profiles of CD4⁻ and CD4⁺ lymphocytes and IFN-α serum levels between wild-type (WT) controls and GHR-KO pigs, which revealed significant differences in the relative proportion of the CD4⁺CD8α⁻ subpopulation and in IFN-α levels. We detected no significant difference in the respiratory capacity and the capacity for polyclonal stimulation in PBMCs between the two groups. But proteome analysis of CD4⁺ and CD4⁻ lymphocyte populations revealed multiple significant protein abundance differences between GHR-KO and WT pigs, involving pathways related to amino acid metabolism, beta-oxidation of fatty acids, insulin secretion signaling, and oxidative phosphorylation. This study highlights the potential use of GHR-KO pigs as a model for studying the effects of impaired GHR signaling on immune functions. Full article

The growth hormone (GH)–insulin-like growth factor-1 (IGF1) signaling pathway plays a major role in orchestrating cellular interactions, metabolism, growth and aging. Studies from worms to mice showed that downregulated activity of the GH/IGF1 pathway could be beneficial for the extension of lifespan. Laron syndrome (LS) is an inherited autosomal recessive disorder caused by molecular defects of the GH receptor (GHR) gene, leading to congenital IGF1 deficiency. Life-long exposure to minute endogenous IGF1 levels in LS is associated with low stature as well as other endocrine and metabolic deficits. Epidemiological surveys reported that patients with LS have a reduced risk of developing cancer. Studies conducted on LS-derived lymphoblastoid cells led to the identification of a novel link between IGF1 and thioredoxin-interacting protein (TXNIP), a multifunctional mitochondrial protein. TXNIP is highly expressed in LS patients and plays a critical role in cellular redox regulation by thioredoxin. Given that IGF1 affects the levels of TXNIP under various stress conditions, including high glucose and oxidative stress, we hypothesized that the IGF1–TXNIP axis plays an essential role in helping maintain a physiological balance in cellular homeostasis. In this study, we show that TXNIP is vital for the cell fate choice when cells are challenged by various stress signals. Furthermore, prolonged IGF1 treatment leads to the establishment of a premature senescence phenotype characterized by a unique senescence network signature. Combined IGF1/TXNIP-induced premature senescence can be associated with a typical secretory inflammatory phenotype that is mediated by STAT3/IL-1A signaling. Finally, these mechanistic insights might help with the understanding of basic aspects of IGF1-related pathologies in the clinical setting. Full article

Normal growth and development in mammals are tightly controlled by numerous genetic factors and metabolic conditions. The growth hormone (GH)-insulin-like growth factor-1 (IGF1) hormonal axis is a key player in the regulation of these processes. Dysregulation of the GH-IGF1 endocrine system is linked to a number of pathologies, ranging from growth deficits to cancer. Laron syndrome (LS) is a type of dwarfism that results from mutation of the GH receptor (GHR) gene, leading to GH resistance and short stature as well as a number of metabolic abnormalities. Of major clinical relevance, epidemiological studies have shown that LS patients do not develop cancer. While the mechanisms associated with cancer protection in LS have not yet been elucidated, genomic analyses have identified a series of metabolic genes that are over-represented in LS patients. We hypothesized that these genes might constitute novel targets for IGF1 action. With a fold-change of 11.09, UDP-glucuronosyltransferase 2B15 (UGT2B15) was the top up-regulated gene in LS. The UGT2B15 gene codes for an enzyme that converts xenobiotic substances into lipophilic compounds and thereby facilitates their clearance from the body. We investigated the regulation of UGT2B15 gene expression by IGF1 and insulin. Both hormones inhibited UGT2B15 mRNA levels in endometrial and breast cancer cell lines. Regulation of UGT2B15 protein levels by IGF1/insulin, however, was more complex and not always correlated with mRNA levels. Furthermore, UGT2B15 expression was dependent on p53 status. Thus, UGT2B15 mRNA levels were higher in cell lines expressing a wild-type p53 compared to cells containing a mutated p53. Animal studies confirmed an inverse correlation between UGT2B15 and p53 levels. In summary, increased UGT2B15 levels in LS might confer upon patient’s protection from genotoxic damage. Full article

Ever since the discoveries that human hair follicles (HFs) display the functional peripheral equivalent of the hypothalamic-pituitary-adrenal axis, exhibit elements of the hypothalamic-pituitary-thyroid axis, and even generate melatonin and prolactin, human hair research has proven to be a treasure chest for the exploration of neurohormone functions. However, growth hormone (GH), one of the dominant neurohormones of human neuroendocrine physiology, remains to be fully explored in this context. This is interesting since it has long been appreciated clinically that excessive GH serum levels induce distinct human skin pathology. Acromegaly, or GH excess, is associated with hypertrichosis, excessive androgen-independent growth of body hair, and hirsutism in females, while dysfunctional GH receptor-mediated signaling (Laron syndrome) is associated with alopecia and prominent HF defects. The outer root sheath keratinocytes have recently been shown to express functional GH receptors. Furthermore, and contrary to its name, recombinant human GH is known to inhibit female human scalp HFs’ growth ex vivo, likely via stimulating the expression of the catagen-inducing growth factor, TGF-β2. These limited available data encourage one to systematically explore the largely uncharted role of GH in human HF biology to uncover nonclassical functions of this core neurohormone in human skin physiology. Full article

The growth hormone (GH)–insulin-like growth factor-1 (IGF1) endocrine axis is a central player in normal growth and metabolism as well as in a number of pathologies, including cancer. The GH–IGF1 hormonal system, in addition, has emerged as a major determinant of lifespan and healthspan. Laron syndrome (LS), the best characterized entity under the spectrum of the congenital IGF1 deficiencies, results from mutation of the GH receptor (GHR) gene, leading to dwarfism, obesity and other defects. Consistent with the key role of IGF1 in cellular proliferation, epidemiological studies have shown that LS patients are protected from cancer development. While reduced expression of components of the GH-IGF1 axis is associated with enhanced longevity in animal models, it is still unknown whether LS is associated with an increased lifespan. MicroRNAs (miRs) are endogenous short non-coding RNAs that regulate the expression of complementary mRNAs. While a number of miRs involved in the regulation of IGF components have been identified, no previous studies have investigated the differential expression of miRs in congenital IGF1 deficiencies. The present study was aimed at identifying miRs that are differentially expressed in LS and that might account for the phenotypic features of LS patients, including longevity. Our genomic analyses provide evidence that miR-132-3p was highly expressed in LS. In addition, we identified SIRT1, a member of the sirtuin family of histone deacetylases, as a target for negative regulation by miR-132-3p. The data was consistent with the notion that low concentrations of IGF1 in LS lead to elevated miR-132-3p levels, with ensuing reduction in SIRT1 gene expression. The impact of the IGF1-miR-132-3p-SIRT1 loop on aging merits further investigation. Full article

Endometrial cancer is the most common gynecologic malignancy in Western countries. The insulin-like growth factor-1 (IGF1) axis has an important role in endometrial cancer biology and emerged as a promising therapeutic target in oncology. However, there is an urgent need to identify biomarkers that may help in patient stratification and prognosis. Laron syndrome (LS) is a type of dwarfism that results from the mutation of the growth hormone receptor (GHR) gene, leading to congenital IGF1 deficiency. While high circulating IGF1 is regarded as a risk factor in cancer, epidemiological studies have shown that LS patients are protected from cancer development. Recent genome-wide profilings conducted on LS-derived lymphoblastoid cells led to the identification of a series of genes whose over- or under-representation in this condition might be mechanistically linked to cancer protection. The olfactory receptor 5 subfamily H member 2 (OR5H2) was the top downregulated gene in LS, its expression level being 5.8-fold lower than in the control cells. In addition to their typical role in the olfactory epithelium, olfactory receptors (ORs) are expressed in multiple tissues and play non-classical roles in various pathologies, including cancer. The aim of our study was to investigate the regulation of OR5H2 gene expression by IGF1 in endometrial cancer. Data showed that IGF1 and insulin stimulate OR5H2 mRNA and the protein levels in uterine cancer cell lines expressing either a wild-type or a mutant p53. OR5H2 silencing led to IGF1R downregulation, with ensuing reductions in the downstream cytoplasmic mediators. In addition, OR5H2 knockdown reduced the proliferation rate and cell cycle progression. Analyses of olfr196 (the mouse orthologue of OR5H2) mRNA expression in animal models of GHR deficiency or GH overexpression corroborated the human data. In summary, OR5H2 emerged as a novel target for positive regulation by IGF1, with potential relevance in endometrial cancer. Full article

Anti-Müllerian hormone (AMH) is secreted by Sertoli or granulosa cells. Recent evidence suggests that AMH may play a role in the pathogenesis of hypogonadotropic hypogonadism (HH) and that its serum levels could help to discriminate HH from delayed puberty. Moreover, the growth hormone (GH)/insulin-like growth factor 1 (IGF1) system may be involved in the function of gonadotropin-releasing hormone (GnRH) neurons, as delayed puberty is commonly found in patients with GH deficiency (GHD) or with Laron syndrome, a genetic form of GH resistance. The comprehension of the stimuli enhancing the migration and secretory activity of GnRH neurons might shed light on the causes of delay of puberty or HH. With these premises, we aimed to better clarify the role of the AMH, GH, and IGF1 on GnRH neuron migration and GnRH secretion, by taking advantage of previously established models of immature (GN11 cell line) and mature (GT1-7 cell line) GnRH neurons. Expression of Amhr, Ghr, and Igf1r genes was confirmed in both cell lines. Cells were then incubated with increasing concentrations of AMH (1.5–150 ng/mL), GH (3–1000 ng/mL), or IGF1 (1.5–150 ng/mL). All hormones were able to support GN11 cell chemomigration. AMH, GH, and IGF1 significantly stimulated GnRH secretion by GT1-7 cells after a 90-min incubation. To the best of our knowledge, this is the first study investigating the direct effects of GH and IGF1 in GnRH neuron migration and of GH in the GnRH secreting pattern. Taken together with previous basic and clinical studies, these findings may provide explanatory mechanisms for data, suggesting that AMH and the GH-IGF1 system play a role in HH or the onset of puberty. Full article

Laron syndrome (LS) is a rare genetic endocrinopathy that results from mutation of the growth hormone receptor (GH-R) gene and is typically associated with dwarfism and obesity. LS is the best characterized entity under the spectrum of the congenital insulin-like growth factor-1 (IGF1) deficiencies. Epidemiological analyses have shown that LS patients do not develop cancer, whereas heterozygous family members have a cancer prevalence similar to the general population. To identify genes and signaling pathways differentially represented in LS that may help delineate a biochemical and molecular basis for cancer protection, we have recently conducted a genome-wide profiling of LS patients. Studies were based on our collection of Epstein–Barr virus (EBV)-immortalized lymphoblastoid cell lines derived from LS patients, relatives and healthy controls. Bioinformatic analyses identified differences in gene expression in several pathways, including apoptosis, metabolic control, cytokine biology, Jak-STAT and PI3K-AKT signaling, etc. Genes involved in the control of cell cycle, motility, growth and oncogenic transformation are, in general, down-regulated in LS. These genetic events seem to have a major impact on the biological properties of LS cells, including proliferation, apoptosis, response to oxidative stress, etc. Furthermore, genomic analyses allowed us to identify novel IGF1 downstream target genes that have not been previously linked to the IGF1 signaling pathway. In summary, by ‘mining’ genomic data from LS patients, we were able to generate clinically-relevant information in oncology and, potentially, related disciplines. Full article

Laron syndrome (LS), or primary growth hormone resistance, is a prototypical congenital insulin-like growth factor 1 (IGF1) deficiency. The recent epidemiological finding that LS patients do not develop cancer is of major scientific and clinical relevance. Epidemiological data suggest that congenital IGF1 deficiency confers protection against the development of malignancies. This ‘experiment of nature’ reflects the critical role of IGF1 in tumor biology. The present review article provides an overview of recently conducted genome-wide profiling analyses aimed at identifying mechanisms and signaling pathways that are directly responsible for the link between life-time low IGF1 levels and protection from tumor development. The review underscores the concept that ‘data mining’ an orphan disease might translate into new developments in oncology. Full article

Growth hormone (GH) promotes body growth by binding with two GH receptors (GHRs) at the cell surface. GHRs interact with Janus kinase, signal transducers, and transcription activators to stimulate metabolic effects and insulin‐like growth factor (IGF) synthesis. However, process dysfunctions in the GH–GHR–IGF-1 axis cause animal dwarfism. If, during the GH process, GHR is not successfully recognized and/or bound, or GHR fails to transmit the GH signal to IGF-1, the GH dysfunction occurs. The goal of this review was to focus on the GHR mutations that lead to failures in the GH–GHR–IGF-1 signal transaction process in the dwarf phenotype. Until now, more than 90 GHR mutations relevant to human short stature (Laron syndrome and idiopathic short stature), including deletions, missense, nonsense, frameshift, and splice site mutations, and four GHR defects associated with chicken dwarfism, have been described. Among the 93 identified mutations of human GHR, 68 occur extracellularly, 13 occur in GHR introns, 10 occur intracellularly, and two occur in the transmembrane. These mutations interfere with the interaction between GH and GHRs, GHR dimerization, downstream signaling, and the expression of GHR. These mutations cause aberrant functioning in the GH-GHR-IGF-1 axis, resulting in defects in the number and diameter of muscle fibers as well as bone development. Full article

Obesity is an excessive accumulation or expansion of adipose tissue (AT) due to an increase in either the size and/or number of its characteristic cell type, the adipocyte. As one of the most significant public health problems of our time, obesity and its associated metabolic complications have demanded that attention be given to finding effective therapeutic options aimed at reducing adiposity or the metabolic dysfunction associated with its accumulation. Growth hormone (GH) has therapeutic potential due to its potent lipolytic effect and resultant ability to reduce AT mass while preserving lean body mass. However, AT and its resident adipocytes are significantly more dynamic and elaborate than once thought and require one not to use the reduction in absolute mass as a readout of efficacy alone. Paradoxically, therapies that reduce GH action may ultimately prove to be healthier, in part because GH also possesses potent anti-insulin activities along with concerns that GH may promote the growth of certain cancers. This review will briefly summarize some of the newer complexities of AT relevant to GH action and describe the current understanding of how GH influences this tissue using data from both humans and mice. We will conclude by considering the therapeutic use of GH or GH antagonists in obesity, as well as important gaps in knowledge regarding GH and AT. Full article