Genome-Wide Profiling of Laron Syndrome Patients Identifies Novel Cancer Protection Pathways

Werner, Haim; Lapkina-Gendler, Lena; Achlaug, Laris; Nagaraj, Karthik; Somri, Lina; Yaron-Saminsky, Danielle; Pasmanik‐Chor, Metsada; Sarfstein, Rive; Laron, Zvi; Yakar, Shoshana

doi:10.3390/cells8060596

Cited by 34 publications

(37 citation statements)

References 90 publications

(91 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Epidemiologic evidences indicated that high serum levels of IGF1 correlate with increased risk of cancer [ 21 , 22 ]. Accordingly, patients affected by Laron syndrome, a disease characterized by congenital deficiency of IGF1, do not develop cancer [ 23 ]. In 1993, Sell and colleagues demonstrated that the simian virus 40 large tumor antigen (SV40 TAg) was unable to transform fibroblasts derived from mouse embryos homozygous for a null mutation of the igf1r gene (R − cells) [ 20 ].…”

Section: The Igf System In Cancermentioning

confidence: 99%

Novel Regulators of the IGF System in Cancer

2021

View full text Add to dashboard Cite

The insulin-like growth factor (IGF) system is a dynamic network of proteins, which includes cognate ligands, membrane receptors, ligand binding proteins and functional downstream effectors. It plays a critical role in regulating several important physiological processes including cell growth, metabolism and differentiation. Importantly, alterations in expression levels or activation of components of the IGF network are implicated in many pathological conditions including diabetes, obesity and cancer initiation and progression. In this review we will initially cover some general aspects of IGF action and regulation in cancer and then focus in particular on the role of transcriptional regulators and novel interacting proteins, which functionally contribute in fine tuning IGF1R signaling in several cancer models. A deeper understanding of the biological relevance of this network of IGF1R modulators might provide novel therapeutic opportunities to block this system in neoplasia.

show abstract

Section: The Igf System In Cancermentioning

confidence: 99%

Novel Regulators of the IGF System in Cancer

2021

View full text Add to dashboard Cite

show abstract

“…This occurs especially in patients with molecular defects in the intracellular GH signaling pathway (STAT5B, STAT3, IKBKB, IL2RG, PIK3R1) [64]. Interestingly, patients with Laron syndrome do not develop cancer [66][67][68][69][70] and recent studies on genome-wide profiling of patients with this syndrome has been able to identify novel cancer protection pathways, opening the way to new developments in oncology [69,70]. These results, together with those of the studies in centenarians [70,71], seem to indicate a preventing effect of reduced secretion or lacking action of GH-IGF-1 on some diseases with increased life expectance.…”

Section: Genetic Alteration Affecting Gh and Igf-1 Actionsmentioning

confidence: 99%

Impact of Pituitary Autoimmunity and Genetic Disorders on Growth Hormone Deficiency in Children and Adults

Bellastella

Maiorino

Longo

et al. 2020

IJMS

View full text Add to dashboard Cite

Growth hormone (GH), mostly through its peripheral mediator, the insulin-like growth factor 1(IGF1), in addition to carrying out its fundamental action to promote linear bone growth, plays an important role throughout life in the regulation of intermediate metabolism, trophism and function of various organs, especially the cardiovascular, muscular and skeletal systems. Therefore, if a prepubertal GH secretory deficiency (GHD) is responsible for short stature, then a deficiency in adulthood identifies a nosographic picture classified as adult GHD syndrome, which is characterized by heart, muscle, bone, metabolic and psychic abnormalities. A GHD may occur in patients with pituitary autoimmunity; moreover, GHD may also be one of the features of some genetic syndromes in association with other neurological, somatic and immune alterations. This review will discuss the impact of pituitary autoimmunity on GHD and the occurrence of GHD in the context of some genetic disorders. Moreover, we will discuss some genetic alterations that cause GH and IGF-1 insensitivity and the arguments in favor and against the influence of GH/IGF-1 on longevity and cancer in the light of the papers on these issues that so far appear in the literature.

show abstract

“…PPP strongly inhibited FO-induced bone formation and growth rate, indicating that FO-mediated bone formation and growth performance require the presence of IGF-1. Recently, Werner et al reported that pituitary-produced GH leads to the secretion of IGF-1 by the liver into the systemic circulation, which causes bone elongation and longitudinal growth [ 33 ]. Mice lacking GH and IGF-1 receptor ( Gh − / − and IGF-1 − / − ) showed greater reduction in bone mass and length compared with the wild-type ( Ghr + / + and IGF-1 + / + ) mice, suggesting that GH and IGF-1 are important for bone formation [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Fermented Oyster Extract Promotes Insulin-Like Growth Factor-1-Mediated Osteogenesis and Growth Rate

et al. 2020

View full text Add to dashboard Cite

Fermented oyster (Crassostrea gigas) extract (FO) prevents ovariectomy-induced osteoporosis by inhibiting osteoclastogenesis and activating osteogenesis. However, the molecular mechanisms underlying FO-mediated bone formation and growth rate are unclear. In the current study, we found that FO significantly upregulated the expression of growth-promoting genes in zebrafish larvae including insulin-like growth factor 1 (zigf-1), insulin-like growth factor binding protein 3 (zigfbp-3), growth hormone-1 (zgh-1), growth hormone receptor-1 (zghr-1), growth hormone receptor alpha (zghra), glucokinase (zgck), and cholecystokinin (zccka). In addition, zebrafish larvae treated with 100 μg/mL FO increased in total body length (3.89 ± 0.13 mm) at 12 days post fertilization (dpf) compared to untreated larvae (3.69 ± 0.02 mm); this effect was comparable to that of the β-glycerophosphate-treated zebrafish larvae (4.00 ± 0.02 mm). Furthermore, FO time- and dose-dependently increased the extracellular release of IGF-1 from preosteoblast MC3T3-E1 cells, which was accompanied by high expression of IGF-1. Pharmacological inhibition of IGF-1 receptor (IGF-1R) using picropodophyllin (PPP) significantly reduced FO-mediated vertebrae formation (from 9.19 ± 0.31 to 5.53 ± 0.35) and growth performance (from 3.91 ± 0.02 to 3.69 ± 0.01 mm) in zebrafish larvae at 9 dpf. Similarly, PPP significantly decreased FO-induced calcium deposition in MC3T3-E1 cells by inhibiting GSK-3β phosphorylation at Ser9. Additionally, DOI hydrochloride, a potent stabilizer of GSK-3β, reduced FO-induced nuclear translocation of RUNX2. Transient knockdown of IGF-1Rα/β using specific silencing RNA also resulted in a significant decrease in calcium deposition and reduction in GSK-3β phosphorylation at Ser9 in MC3T3-E1 cells. Altogether, these results indicate that FO increased phosphorylated GSK-3β at Ser9 by activating the autocrine IGF-1-mediated IGF-1R signaling pathway, thereby promoting osteogenesis and growth performance. Therefore, FO is a potential nutritional supplement for bone formation and growth.

show abstract

Genome-Wide Profiling of Laron Syndrome Patients Identifies Novel Cancer Protection Pathways

Cited by 34 publications

References 90 publications

Novel Regulators of the IGF System in Cancer

Novel Regulators of the IGF System in Cancer

Impact of Pituitary Autoimmunity and Genetic Disorders on Growth Hormone Deficiency in Children and Adults

Fermented Oyster Extract Promotes Insulin-Like Growth Factor-1-Mediated Osteogenesis and Growth Rate

Contact Info

Product

Resources

About