Laron Syndrome Research Paves the Way for New Insights in Oncological Investigation

Werner, Haim; Sarfstein, Rive; Nagaraj, Karthik; Laron, Zvi

doi:10.3390/cells9112446

Cited by 19 publications

(23 citation statements)

References 90 publications

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“…The Laron syndrome constitutes the best characterized entity under the umbrella of the IGF1 pathologies [ 21 ]. Comprehensive analyses of this disease over half a century have had a major impact on our current understanding of normal and aberrant growth [ 43 , 62 , 63 ].…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA 132-3p Is Upregulated in Laron Syndrome Patients and Controls Longevity Gene Expression

Yaron-Saminsky

Nagaraj

Sarfstein

et al. 2021

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%

“…In addition, a number of genes usually involved in growth promotion were shown to be under-represented in LS [ 41 , 42 ]. Of notice, these genes have not been previously linked to the IGF1 signaling axis [ 43 ].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA 132-3p Is Upregulated in Laron Syndrome Patients and Controls Longevity Gene Expression

Yaron-Saminsky

Nagaraj

Sarfstein

et al. 2021

IJMS

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“…In contrast, patients with Laron syndrome, who present dwarfism due to a genetic loss-of-function mutation of GHR [219,220] , exhibit failures in the GH-GHR-IGF-1 signal transduction process, resulting in congenital IGF-1 deficiency associated with a reduced incidence of cancers including PCa [221][222][223][224] . Notably, disruption of GH signaling retards early stages of prostate carcinogenesis in the C3(1)/T antigen mouse and Probasin/TAg rat model [225,226] .…”

Section: Growth Hormonementioning

confidence: 99%

The endocrine and epigenetic impact of persistent cow milk consumption on prostate carcinogenesis

Melnik¹,

John²,

Weiskirchen³

et al. 2022

jtgg

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This review analyzes the potential impact of milk-induced signal transduction on the pathogenesis of prostate cancer (PCa). Articles in PubMed until November 2021 reporting on milk intake and PCa were reviewed. Epidemiological studies identified commercial cow milk consumption as a potential risk factor of PCa. The potential impact of cow milk consumption on the pathogenesis of PCa may already begin during fetal and pubertal prostate growth, critical windows with increased vulnerability. Milk is a promotor of growth and anabolism via activating insulin-like growth factor-1 (IGF-1)/phosphatidylinositol-3 kinase (PI3K)/AKT/mechanistic target of rapamycin complex 1 (mTORC1) signaling. Estrogens, major steroid hormone components of commercial milk of persistently pregnant dairy cows, activate IGF-1 and mTORC1. Milk-derived signaling synergizes with common driver mutations of the PI3K/AKT/mTORC1 signaling pathway that intersect with androgen receptor, MFG-E8, MAPK, RUNX2, MDM4, TP53, and WNT signaling, respectively. Potential exogenously induced drivers of PCa are milk-induced elevations of growth hormone, IGF-1, MFG-E8, estrogens, phytanic acid, and aflatoxins, as well as milk exosome-derived oncogenic microRNAs including miR-148a, miR-21, and miR-29b. Commercial cow milk intake, especially the consumption of pasteurized milk, which represents the closest replica of native milk, activates PI3K-AKT-mTORC1 signaling via cow milk’s endocrine and epigenetic modes of action. Vulnerable periods for adverse nutrigenomic impacts on prostate health appear to be the fetal and pubertal growth periods, potentially priming the initiation of PCa. Cow milk-mediated overactivation of PI3K-AKT-mTORC1 signaling synergizes with the most common genetic deviations in PCa, promoting PCa initiation, progression, and early recurrence.

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“…Much of what is known about the function of IGF-1 has been established through studies of IGF-1 deficiencies [36,37] that can arise as a result of many different abnormalities in the hormones and receptors responsible for normal healthy growth [38][39][40]. Con- Network of experimentally confirmed (purple lines) and documented (blue lines) protein-protein interaction (PPI) of insulin-like growth factor-1 (IGF-1) generated with string-db.org.…”

Section: Igf-1 As a Marker In Medical Conditions And Diseasementioning

confidence: 99%

“…The most common form of SPIGFD is known as Laron syndrome and results from a mutation to the GHR gene, rendering the affected individual insensitive to GH. Children diagnosed with Laron syndrome can be treated with recombinant IGF-1 [ 38 , 40 ]. Additional conditions under the umbrella of congenital IGF-1 deficiencies include a documented case of a 15-year-old boy suffering from severe prenatal and postnatal growth failure, sensorineural deafness and mental retardation due to a homozygous partial deletion of the IGF-I gene [ 41 ] as well as IGF1R genes defects [ 42 ].…”

Section: Igf-1 As a Marker In Medical Conditions And Diseasementioning

confidence: 99%

Insulin-Like Growth Factor-1 (IGF-1) and Its Monitoring in Medical Diagnostic and in Sports

Bailes

Soloviev

2021

Biomolecules

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Insulin-like growth factor-1 (IGF-1) is the principal mediator of growth hormone (GH), plays a crucial role in promoting cell growth and differentiation in childhood and continues to have an anabolic effect in adults. IGF-1 is part of a wide network of growth factors, receptors and binding proteins involved in mediating cellular proliferation, differentiation and apoptosis. Bioavailability of IGF-1 is affected by insulin-like growth factor binding proteins (IGFBPs) which bind IGF-1 in circulation with an affinity equal to or greater than that of the IGF-1 receptor (IGF-1R). The six IGFBPs serve as carrier proteins and bind approximately 98% of all circulating IGF-1. Other proteins known to bind IGF-1 include ten IGFBP-related proteins (IGFBP-rPs), albeit with lower affinities than the IGFBPs. IGF-1 expression levels vary in a number of clinical conditions suggesting it has the potential to provide crucial information as to the state of an individual’s health. IGF-1 is also a popular doping agent in sport and has featured in many high-profile doping cases in recent years. However, the existence of IGFBPs significantly reduces the levels of immunoreactive IGF-1 in samples, requiring multiple pre-treatment steps that reduce reproducibility and complicates interpretation of IGF-1 assay results. Here we provide an overview of the IGF network of growth factors, their receptors and the entirety of the extended family of IGFBPs, IGFBP-rPs, E peptides as well as recombinant IGF-1 and their derivatives. We also discuss issues related to the detection and quantification of bioavailable IGF-1.

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Laron Syndrome Research Paves the Way for New Insights in Oncological Investigation

Cited by 19 publications

References 90 publications

MicroRNA 132-3p Is Upregulated in Laron Syndrome Patients and Controls Longevity Gene Expression

MicroRNA 132-3p Is Upregulated in Laron Syndrome Patients and Controls Longevity Gene Expression

The endocrine and epigenetic impact of persistent cow milk consumption on prostate carcinogenesis

Insulin-Like Growth Factor-1 (IGF-1) and Its Monitoring in Medical Diagnostic and in Sports

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