Abstract
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.
Highlights
As the same mutation was found in a Jewish majority of Laron syndrome (LS) patients from the Ecuadorian cohort are homozygous for an A to G splice site mutation girl of Moroccan origin, it is assumed that the gene was brought to South and Central America by at position 180 in exon 6 of the GH receptor (GHR) gene [55]
The analyses revealed that none of the 230 LS patients had developed a malignancy, despite the fact that 66 of them had been treated with insulin-like growth factor-1 (IGF1) and two had received hGH
Our analyses identified a number of genes that in lymphoblastoid cells of LS patients compared to healthy controls of the same gender, age, and ethnic are differentially expressed in lymphoblastoid cells of LS patients compared to healthy controls of group
Summary
The biological actions of the growth hormone (GH)-insulin-like growth factor-1 (IGF1) axis have been clearly delineated [1,2]. In addition to its classic endocrine mode of action, a number of extrahepatic tissues display the biosynthetic machinery necessary to produce IGF1. IGF1 and IGF2 activate a common cell-surface receptor, the IGF1 receptor (IGF1R). Activation (i.e., phosphorylation) of the IGF1R tyrosine kinase domain by either IGF1 or IGF2 leads to the subsequent activation of a cytoplasmic enzymatic cascade that is directly responsible for the execution of the metabolic and growth actions of hormones [11,12]. The IGF2 receptor (IGF2R) is identical to the mannose 6-phosphate receptor, a cell-surface protein that binds IGF2 with high affinity and targets it for lysosomal degradation [17,18]. The analyses presented here are aimed at delineating a molecular signature associated with cancer protection
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