Insulin-Like Growth Factors in Development, Cancers and Aging

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cellular Aging".

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Editor

Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Interests: insulin-like growth factors; IGF1 receptor; mechanisms of transcription; tumor suppressors
Special Issues, Collections and Topics in MDPI journals

Topical Collection Information

Dear Colleagues,

Since their discovery in the late 1950s, insulin-like growth factors (IGF) have generated a significant level of interest in many areas of biology and medicine, including endocrinology; pediatrics; growth and development; metabolism; nutrition; aging and longevity; and, finally, cancer research. IGF1, which was initially identified as the mediator of growth hormone action, is regarded as a key player in numerous cellular and organismal processes. The signaling pathways elicited by IGF1 have been extensively characterized in biochemical and molecular terms over the past 40 years. However, fundamental questions regarding basic differences between mechanisms of action of IGF1 and the closely related insulin molecule are yet to be resolved. IGF1 displays one of the most potent anti-apoptotic and pro-survival activities amongst all growth factors identified to date. Therefore, the IGF1 axis and, in particular, the IGF1 receptor emerged as a promising therapeutic target in oncology. In addition, the IGF1 system plays an important role in aging processes and abrogation of the growth hormone-IGF1 endocrine axis is associated with increased lifespan. This Topic Collection of Cells will provide a collection of modern articles dealing with the role of IGF1 action in cancer biology, aging, and development. The articles explore basic and clinical aspects of the IGF1 system, including post-genomic analyses as well as novel, personalized approaches to target the IGF1R in oncology.

Prof. Haim Werner
Collection Editor

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Keywords

  • insulin-like growth factors (IGF1, IGF2)
  • IGF1 receptor
  • IGF binding proteins
  • mechanisms of cancer
  • personalized medicine
  • targeted therapy
  • longevity
  • aging
  • development

Related Special Issue

Published Papers (16 papers)

2023

Jump to: 2022, 2021

15 pages, 2238 KiB  
Article
Sustained Nrf2 Overexpression-Induced Metabolic Deregulation Can Be Attenuated by Modulating Insulin/Insulin-like Growth Factor Signaling
by Sentiljana Gumeni, Maria Lamprou, Zoi Evangelakou, Maria S. Manola and Ioannis P. Trougakos
Cells 2023, 12(22), 2650; https://doi.org/10.3390/cells12222650 - 18 Nov 2023
Viewed by 837
Abstract
The modulation of insulin/insulin-like growth factor signaling (IIS) is associated with altered nutritional and metabolic states. The Drosophila genome encodes eight insulin-like peptides, whose activity is regulated by a group of secreted factors, including Ecdysone-inducible gene L2 (ImpL2), which acts as [...] Read more.
The modulation of insulin/insulin-like growth factor signaling (IIS) is associated with altered nutritional and metabolic states. The Drosophila genome encodes eight insulin-like peptides, whose activity is regulated by a group of secreted factors, including Ecdysone-inducible gene L2 (ImpL2), which acts as a potent IIS inhibitor. We recently reported that cncC (cncC/Nrf2), the fly ortholog of Nrf2, is a positive transcriptional regulator of ImpL2, as part of a negative feedback loop aiming to suppress cncC/Nrf2 activity. This finding correlated with our observation that sustained cncC/Nrf2 overexpression/activation (cncCOE; a condition that signals organismal stress) deregulates IIS, causing hyperglycemia, the exhaustion of energy stores in flies’ tissues, and accelerated aging. Here, we extend these studies in Drosophila by assaying the functional implication of ImpL2 in cncCOE-mediated metabolic deregulation. We found that ImpL2 knockdown (KD) in cncCOE flies partially reactivated IIS, attenuated hyperglycemia and restored tissue energetics. Moreover, ImpL2 KD largely suppressed cncCOE-mediated premature aging. In support, pharmacological treatment of cncCOE flies with Metformin, a first-line medication for type 2 diabetes, restored (dose-dependently) IIS functionality and extended cncCOE flies’ longevity. These findings exemplify the effect of chronic stress in predisposition to diabetic phenotypes, indicating the potential prophylactic role of maintaining normal IIS functionality. Full article
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25 pages, 3874 KiB  
Article
Phosphorylation of IGFBP-3 by Casein Kinase 2 Blocks Its Interaction with Hyaluronan, Enabling HA-CD44 Signaling Leading to Increased NSCLC Cell Survival and Cisplatin Resistance
by Kai-ling Coleman, Michael Chiaramonti, Ben Haddad, Robert Ranzenberger, Heather Henning, Hind Al Khashali, Ravel Ray, Ban Darweesh, Jeffrey Guthrie, Deborah Heyl and Hedeel Guy Evans
Cells 2023, 12(3), 405; https://doi.org/10.3390/cells12030405 - 25 Jan 2023
Cited by 3 | Viewed by 1822
Abstract
Cisplatin is a platinum agent used in the treatment of non-small cell lung cancer (NSCLC). Much remains unknown regarding the basic operative mechanisms underlying cisplatin resistance in NSCLC. In this study, we found that phosphorylation of IGFBP-3 by CK2 (P-IGFBP-3) decreased its binding [...] Read more.
Cisplatin is a platinum agent used in the treatment of non-small cell lung cancer (NSCLC). Much remains unknown regarding the basic operative mechanisms underlying cisplatin resistance in NSCLC. In this study, we found that phosphorylation of IGFBP-3 by CK2 (P-IGFBP-3) decreased its binding to hyaluronan (HA) but not to IGF-1 and rendered the protein less effective at reducing cell viability or increasing apoptosis than the non-phosphorylated protein with or without cisplatin in the human NSCLC cell lines, A549 and H1299. Our data suggest that blocking CD44 signaling augmented the effects of cisplatin and that IGFBP-3 was more effective at inhibiting HA-CD44 signaling than P-IGFBP-3. Blocking CK2 activity and HA-CD44 signaling increased cisplatin sensitivity and more effectively blocked the PI3K and AKT activities and the phospho/total NFκB ratio and led to increased p53 activation in A549 cells. Increased cell sensitivity to cisplatin was observed upon co-treatment with inhibitors targeted against PI3K, AKT, and NFκB while blocking p53 activity decreased A549 cell sensitivity to cisplatin. Our findings shed light on a novel mechanism employed by CK2 in phosphorylating IGFBP-3 and increasing cisplatin resistance in NSCLC. Blocking phosphorylation of IGFBP-3 by CK2 may be an effective strategy to increase NSCLC sensitivity to cisplatin. Full article
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2022

Jump to: 2023, 2021

14 pages, 2315 KiB  
Article
Insulin-like Growth Factor Binding Protein 3 Increases Mouse Preimplantation Embryo Cleavage Rate by Activation of IGF1R and EGFR Independent of IGF1 Signalling
by Charmaine J. Green, Miriam Span, Monique H. Rayhanna, Marisa Perera and Margot L. Day
Cells 2022, 11(23), 3762; https://doi.org/10.3390/cells11233762 - 24 Nov 2022
Viewed by 1335
Abstract
The viability of embryos cultured in vitro is poor compared to those that develop in vivo. The lack of maternally derived growth factors in vitro may contribute to this problem. Insulin-like growth factor binding protein 3 (IGFBP3) is one such growth factor [...] Read more.
The viability of embryos cultured in vitro is poor compared to those that develop in vivo. The lack of maternally derived growth factors in vitro may contribute to this problem. Insulin-like growth factor binding protein 3 (IGFBP3) is one such growth factor that has been identified in the maternal reproductive system. This study examined the role of autocrine and exogenous IGFBP3 in mouse preimplantation embryos. Embryos expressed IGFBP3 across all stages of preimplantation development, and addition of exogenous IGFBP3 to embryo culture media increased the rate of development to the 2-, 4-, 5-, and 8-cell stages. Addition of inhibitors of the IGF1 and EGF receptors prevented this IGFBP3-mediated improvement in developmental rate, but the effect was not cumulative, indicating that both receptors are transactivated downstream of IGFBP3 as part of the same signalling pathway. Acute exposure to IGFBP3 increased phosphorylation of Akt and rps6 in 4–8 cell embryos, suggesting activation of the PI3-kinase/Akt pathway downstream of the IGF1 and EGFR receptors to promote cell proliferation and survival. In conclusion, addition of IGFBP3 to embryo culture media increases early cleavage rates independent of IGF1 signalling and therefore, IGFBP3 addition to IVF culture media should be considered. Full article
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22 pages, 2992 KiB  
Article
Opposing Roles of IGFBP-3 and Heparanase in Regulating A549 Lung Cancer Cell Survival
by Hind Al Khashali, Jadziah Wareham, Ravel Ray, Ben Haddad, Kai-Ling Coleman, Robert Ranzenberger, Patrick McCombs, Jeffrey Guthrie, Deborah Heyl and Hedeel Guy Evans
Cells 2022, 11(22), 3533; https://doi.org/10.3390/cells11223533 - 08 Nov 2022
Cited by 5 | Viewed by 1859
Abstract
In this study, we examined the roles of heparanase and IGFBP-3 in regulating A549 and H1299 non-small-cell lung cancer (NSCLC) survival. We found that H1299 cells, known to be p53-null with no expression of IGFBP-3, had higher heparanase levels and activity and higher [...] Read more.
In this study, we examined the roles of heparanase and IGFBP-3 in regulating A549 and H1299 non-small-cell lung cancer (NSCLC) survival. We found that H1299 cells, known to be p53-null with no expression of IGFBP-3, had higher heparanase levels and activity and higher levels of heparan sulfate (HS) in the media compared to the media of A549 cells. Inhibiting heparanase activity or its expression using siRNA had no effect on the levels of IGFBP-3 in the media of A549 cells, reduced the levels of soluble HS fragments, and led to decreased interactions between IGFBP-3 and HS in the media. HS competed with HA for binding to IGFBP-3 or IGFBP-3 peptide (215-KKGFYKKKQCRPSKGRKR-232) but not the mutant peptide (K228AR230A). HS abolished the cytotoxic effects of IGFBP-3 but not upon blocking HA–CD44 signaling with the anti-CD44 antibody (5F12). Blocking HA–CD44 signaling decreased the levels of heparanase in the media of both A549 and H1299 cell lines and increased p53 activity and the levels of IGFBP-3 in A549 cell media. Knockdown of p53 led to increased heparanase levels and reduced IGFBP-3 levels in A549 cell media while knockdown of IGFBP-3 in A549 cells blocked p53 activity and increased heparanase levels in the media. Full article
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23 pages, 4001 KiB  
Article
Long-Term IGF1 Stimulation Leads to Cellular Senescence via Functional Interaction with the Thioredoxin-Interacting Protein, TXNIP
by Karthik Nagaraj, Rive Sarfstein, Zvi Laron and Haim Werner
Cells 2022, 11(20), 3260; https://doi.org/10.3390/cells11203260 - 17 Oct 2022
Cited by 4 | Viewed by 2711
Abstract
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 [...] Read more.
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
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18 pages, 3554 KiB  
Article
Early Dietary Exposures Epigenetically Program Mammary Cancer Susceptibility through Igf1-Mediated Expansion of the Mammary Stem Cell Compartment
by Yuanning Zheng, Linjie Luo, Isabel U. Lambertz, Claudio J. Conti and Robin Fuchs-Young
Cells 2022, 11(16), 2558; https://doi.org/10.3390/cells11162558 - 17 Aug 2022
Cited by 4 | Viewed by 1468
Abstract
Diet is a critical environmental factor affecting breast cancer risk, and recent evidence shows that dietary exposures during early development can affect lifetime mammary cancer susceptibility. To elucidate the underlying mechanisms, we used our established crossover feeding mouse model, where exposure to a [...] Read more.
Diet is a critical environmental factor affecting breast cancer risk, and recent evidence shows that dietary exposures during early development can affect lifetime mammary cancer susceptibility. To elucidate the underlying mechanisms, we used our established crossover feeding mouse model, where exposure to a high-fat and high-sugar (HFHS) diet during defined developmental windows determines mammary tumor incidence and latency in carcinogen-treated mice. Mammary tumor incidence is significantly increased in mice receiving a HFHS post-weaning diet (high-tumor mice, HT) compared to those receiving a HFHS diet during gestation (low-tumor mice, LT). The current study revealed that the mammary stem cell (MaSC) population was significantly increased in mammary glands from HT compared to LT mice. Igf1 expression was increased in mammary stromal cells from HT mice, where it promoted MaSC self-renewal. The increased Igf1 expression was induced by DNA hypomethylation of the Igf1 Pr1 promoter, mediated by a decrease in Dnmt3b levels. Mammary tissues from HT mice also had reduced levels of Igfbp5, leading to increased bioavailability of tissue Igf1. This study provides novel insights into how early dietary exposures program mammary cancer risk, demonstrating that effective dietary intervention can reduce mammary cancer incidence. Full article
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18 pages, 1893 KiB  
Review
IGF2: Development, Genetic and Epigenetic Abnormalities
by Céline Sélénou, Frédéric Brioude, Eloïse Giabicani, Marie-Laure Sobrier and Irène Netchine
Cells 2022, 11(12), 1886; https://doi.org/10.3390/cells11121886 - 10 Jun 2022
Cited by 15 | Viewed by 5796
Abstract
In the 30 years since the first report of parental imprinting in insulin-like growth factor 2 (Igf2) knockout mouse models, we have learnt much about the structure of this protein, its role and regulation. Indeed, many animal and human studies involving [...] Read more.
In the 30 years since the first report of parental imprinting in insulin-like growth factor 2 (Igf2) knockout mouse models, we have learnt much about the structure of this protein, its role and regulation. Indeed, many animal and human studies involving innovative techniques have shed light on the complex regulation of IGF2 expression. The physiological roles of IGF-II have also been documented, revealing pleiotropic tissue-specific and developmental-stage-dependent action. Furthermore, in recent years, animal studies have highlighted important interspecies differences in IGF-II function, gene expression and regulation. The identification of human disorders due to impaired IGF2 gene expression has also helped to elucidate the major role of IGF-II in growth and in tumor proliferation. The Silver–Russell and Beckwith–Wiedemann syndromes are the most representative imprinted disorders, as they constitute both phenotypic and molecular mirrors of IGF2-linked abnormalities. The characterization of patients with either epigenetic or genetic defects altering IGF2 expression has confirmed the central role of IGF-II in human growth regulation, particularly before birth, and its effects on broader body functions, such as metabolism or tumor susceptibility. Given the long-term health impact of these rare disorders, it is important to understand the consequences of IGF2 defects in these patients. Full article
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14 pages, 2664 KiB  
Article
Identification of UDP-Glucuronosyltransferase 2B15 (UGT2B15) as a Target for IGF1 and Insulin Action
by Rive Sarfstein, Karthik Nagaraj, Shivang Parikh, Carmit Levy, Zvi Laron, Dafna Benayahu and Haim Werner
Cells 2022, 11(10), 1627; https://doi.org/10.3390/cells11101627 - 12 May 2022
Cited by 2 | Viewed by 1924
Abstract
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 [...] Read more.
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
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13 pages, 3392 KiB  
Article
Essential Amino Acid Intake Is Required for Sustaining Serum Insulin-like Growth Factor-I Levels but Is Not Necessarily Needed for Body Growth
by Hiroki Nishi, Kaito Uchida, Maki Saito, Daisuke Yamanaka, Haruka Nagata, Hinako Tomoshige, Ichiro Miyata, Koichi Ito, Yuka Toyoshima, Shin-Ichiro Takahashi, Fumihiko Hakuno and Asako Takenaka
Cells 2022, 11(9), 1523; https://doi.org/10.3390/cells11091523 - 02 May 2022
Cited by 3 | Viewed by 3063
Abstract
Essential amino acids (EAAs) are those that cannot be synthesized enough to meet organismal demand; therefore, it is believed that they must be taken from the diet for optimal growth. The growth hormone (GH)/insulin-like growth factor-I (IGF-I) system is also considered significant for [...] Read more.
Essential amino acids (EAAs) are those that cannot be synthesized enough to meet organismal demand; therefore, it is believed that they must be taken from the diet for optimal growth. The growth hormone (GH)/insulin-like growth factor-I (IGF-I) system is also considered significant for growth regulation in mammals. This study aimed to evaluate the relative contributions of protein nutrition and the GH/IGF-I system to body growth regulation. Experiments using rodents and hepatocyte-derived cell lines subjected to EAA deficiency showed that a reduction in the serum EAA concentration hinders Igf1 transcription in the liver in a cell-autonomous manner, thereby decreasing serum IGF-I levels. Remarkably, when the serum IGF-I level of mice on a low-protein diet was restored by the recombinant IGF-I infusion, the body growth was mostly rescued, although the mice were still deficient in EAA intake. Meanwhile, the GH signal activation and subsequent Igf1 transcription were also dramatically diminished by EAA deprivation in the cell culture model. Altogether, we demonstrate that EAAs are not strictly necessary for animal growth as building blocks but are required as IGF-I-tropic cues. The results will bring a paradigm shift regarding the definition of “essential” amino acids. Full article
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2021

Jump to: 2023, 2022

16 pages, 1234 KiB  
Review
Growth Hormone and IGF1 Actions in Kidney Development and Function
by Evgenia Gurevich, Yael Segev and Daniel Landau
Cells 2021, 10(12), 3371; https://doi.org/10.3390/cells10123371 - 30 Nov 2021
Cited by 11 | Viewed by 3617
Abstract
Growth hormone (GH) exerts multiple effects on different organs including the kidneys, either directly or via its main mediator, insulin-like-growth factor-1 (IGF-1). The GH/IGF1 system plays a key role in normal kidney development, glomerular hemodynamic regulation, as well as tubular water, sodium, phosphate, [...] Read more.
Growth hormone (GH) exerts multiple effects on different organs including the kidneys, either directly or via its main mediator, insulin-like-growth factor-1 (IGF-1). The GH/IGF1 system plays a key role in normal kidney development, glomerular hemodynamic regulation, as well as tubular water, sodium, phosphate, and calcium handling. Transgenic animal models demonstrated that GH excess (and not IGF1) may lead to hyperfiltration, albuminuria, and glomerulosclerosis. GH and IGF-1 play a significant role in the early development of diabetic nephropathy, as well as in compensatory kidney hypertrophy after unilateral nephrectomy. Chronic kidney disease (CKD) and its complications in children are associated with alterations in the GH/IGF1 axis, including growth retardation, related to a GH-resistant state, attributed to impaired kidney postreceptor GH-signaling and chronic inflammation. This may explain the safety of prolonged rhGH-treatment of short stature in CKD. Full article
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13 pages, 305 KiB  
Review
The Role of Insulin-like Growth Factor-1 (IGF-1) in the Control of Neuroendocrine Regulation of Growth
by Sarmed Al-Samerria and Sally Radovick
Cells 2021, 10(10), 2664; https://doi.org/10.3390/cells10102664 - 05 Oct 2021
Cited by 41 | Viewed by 5856
Abstract
In mammals, the neuroendocrine system, which includes the communication between the hypothalamus and the pituitary, plays a major role in controlling body growth and cellular metabolism. GH produced from the pituitary somatotroph is considered the master regulator of somatic development and involved, directly [...] Read more.
In mammals, the neuroendocrine system, which includes the communication between the hypothalamus and the pituitary, plays a major role in controlling body growth and cellular metabolism. GH produced from the pituitary somatotroph is considered the master regulator of somatic development and involved, directly and indirectly, in carbohydrate and lipid metabolism via complex, yet well-defined, signaling pathways. GH production from the pituitary gland is primarily regulated by the counter-regulatory effects of the hypothalamic GHRH and SST hormones. The role of IGF-1 feedback regulation in GH production has been demonstrated by pharmacologic interventions and in genetically modified mouse models. In the present review, we discuss the role of IGF-1 in the regulation of the GH-axis as it controls somatic growth and metabolic homeostasis. We present genetically modified mouse models that maintain the integrity of the GH/GHRH-axis with the single exception of IGF-1 receptor (IGF-1R) deficiency in the hypothalamic GHRH neurons and somatotroph that reveals a novel mechanism controlling adipose tissues physiology and energy expenditure. Full article
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24 pages, 1472 KiB  
Review
Applying Bioinformatic Platforms, In Vitro, and In Vivo Functional Assays in the Characterization of Genetic Variants in the GH/IGF Pathway Affecting Growth and Development
by Sabina Domené, Paula A. Scaglia, Mariana L. Gutiérrez and Horacio M. Domené
Cells 2021, 10(8), 2063; https://doi.org/10.3390/cells10082063 - 12 Aug 2021
Cited by 7 | Viewed by 2518
Abstract
Heritability accounts for over 80% of adult human height, indicating that genetic variability is the main determinant of stature. The rapid technological development of Next-Generation Sequencing (NGS), particularly Whole Exome Sequencing (WES), has resulted in the characterization of several genetic conditions affecting growth [...] Read more.
Heritability accounts for over 80% of adult human height, indicating that genetic variability is the main determinant of stature. The rapid technological development of Next-Generation Sequencing (NGS), particularly Whole Exome Sequencing (WES), has resulted in the characterization of several genetic conditions affecting growth and development. The greatest challenge of NGS remains the high number of candidate variants identified. In silico bioinformatic tools represent the first approach for classifying these variants. However, solving the complicated problem of variant interpretation requires the use of experimental approaches such as in vitro and, when needed, in vivo functional assays. In this review, we will discuss a rational approach to apply to the gene variants identified in children with growth and developmental defects including: (i) bioinformatic tools; (ii) in silico modeling tools; (iii) in vitro functional assays; and (iv) the development of in vivo models. While bioinformatic tools are useful for a preliminary selection of potentially pathogenic variants, in vitro—and sometimes also in vivo—functional assays are further required to unequivocally determine the pathogenicity of a novel genetic variant. This long, time-consuming, and expensive process is the only scientifically proven method to determine causality between a genetic variant and a human genetic disease. Full article
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11 pages, 660 KiB  
Article
Dysregulation of miRNAs Targeting the IGF-1R Pathway in Pancreatic Ductal Adenocarcinoma
by Maria Dobre, Vlad Herlea, Cătălina Vlăduţ, Mihai Ciocîrlan, Vasile Daniel Balaban, Gabriel Constantinescu, Mircea Diculescu and Elena Milanesi
Cells 2021, 10(8), 1856; https://doi.org/10.3390/cells10081856 - 22 Jul 2021
Cited by 11 | Viewed by 2031
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC), the most prevalent neoplastic lethal pancreatic disease, has a poor prognosis and an increasing incidence. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is considered to be a contributing factor to the progression, metastasis, and therapy resistance of [...] Read more.
Background: Pancreatic ductal adenocarcinoma (PDAC), the most prevalent neoplastic lethal pancreatic disease, has a poor prognosis and an increasing incidence. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is considered to be a contributing factor to the progression, metastasis, and therapy resistance of PDAC. Currently available treatment options for PDAC are limited, but microRNAs (miRNAs) may represent a new therapeutic strategy for targeting genes involved in the IGF-1R signaling pathway. Method: We investigated the expression levels of 21 miRNAs involved in the IGF-1R signaling pathway in pancreatic tissue from 38 patients with PDAC and 11 controls (five patients with chronic pancreatitis and six patients with normal pancreatic tissue). Results: We found 19 differentially expressed miRNAs between the PDAC cases and the controls. In particular, miR-100-5p, miR-145-5p, miR-29c-3p, miR-9-5p, and miR-195-5p were exclusively downregulated in PDAC tissue but not in chronic pancreatitis or normal pancreatic tissues; both control types presented similar levels. We also identified miR-29a-3p, miR-29b-3p, and miR-7-5p as downregulated miRNAs in PDAC tissues as compared with normal tissues but not with pancreatitis tissues. Conclusions: We identified a panel of miRNAs that could represent putative therapeutic targets for the development of new miRNA-based therapies for PDAC. Full article
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16 pages, 7289 KiB  
Article
IGF-1 Haploinsufficiency Causes Age-Related Chronic Cochlear Inflammation and Increases Noise-Induced Hearing Loss
by Adelaida M. Celaya, Lourdes Rodríguez-de la Rosa, Jose M. Bermúdez-Muñoz, José M. Zubeldia, Carlos Romá-Mateo, Carlos Avendaño, Federico V. Pallardó and Isabel Varela-Nieto
Cells 2021, 10(7), 1686; https://doi.org/10.3390/cells10071686 - 03 Jul 2021
Cited by 12 | Viewed by 3459
Abstract
Insulin-like growth factor 1 (IGF-1) deficiency is an ultrarare syndromic human sensorineural deafness. Accordingly, IGF-1 is essential for the postnatal maturation of the cochlea and the correct wiring of hearing in mice. Less severe decreases in human IGF-1 levels have been associated with [...] Read more.
Insulin-like growth factor 1 (IGF-1) deficiency is an ultrarare syndromic human sensorineural deafness. Accordingly, IGF-1 is essential for the postnatal maturation of the cochlea and the correct wiring of hearing in mice. Less severe decreases in human IGF-1 levels have been associated with other hearing loss rare genetic syndromes, as well as with age-related hearing loss (ARHL). However, the underlying mechanisms linking IGF-1 haploinsufficiency with auditory pathology and ARHL have not been studied. Igf1-heterozygous mice express less Igf1 transcription and have 40% lower IGF-1 serum levels than wild-type mice. Along with ageing, IGF-1 levels decreased concomitantly with the increased expression of inflammatory cytokines, Tgfb1 and Il1b, but there was no associated hearing loss. However, noise exposure of these mice caused increased injury to sensory hair cells and irreversible hearing loss. Concomitantly, there was a significant alteration in the expression ratio of pro- and anti-inflammatory cytokines in Igf1+/− mice. Unbalanced inflammation led to the activation of the stress kinase JNK and the failure to activate AKT. Our data show that IGF-1 haploinsufficiency causes a chronic subclinical proinflammatory age-associated state and, consequently, greater susceptibility to stressors. This work provides the molecular bases to further understand hearing disorders linked to IGF-1 deficiency. Full article
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14 pages, 2991 KiB  
Article
The Olfactory Receptor Gene Product, OR5H2, Modulates Endometrial Cancer Cells Proliferation via Interaction with the IGF1 Signaling Pathway
by Rand Shibel, Rive Sarfstein, Karthik Nagaraj, Lena Lapkina-Gendler, Zvi Laron, Manisha Dixit, Shoshana Yakar and Haim Werner
Cells 2021, 10(6), 1483; https://doi.org/10.3390/cells10061483 - 12 Jun 2021
Cited by 10 | Viewed by 2820
Abstract
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 [...] Read more.
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
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20 pages, 3236 KiB  
Article
Development of a Sensitive Bioassay for the Analysis of IGF-Related Activation of AKT/mTOR Signaling in Biological Matrices
by Michael Walz, Christine Höflich, Christina Walz, Daniela Ohde, Julia Brenmoehl, Mandy Sawitzky, Andreas Vernunft, Uwe K. Zettl, Susanne Holtze, Thomas B. Hildebrandt, Eckhard Wolf and Andreas Hoeflich
Cells 2021, 10(3), 482; https://doi.org/10.3390/cells10030482 - 24 Feb 2021
Cited by 3 | Viewed by 2456
Abstract
The bioactivity of the IGF system is not a function of isolated hormone concentrations in a given biological matrix. Instead, the biological activities of IGFs are regulated by IGFBPs, IGFBP proteases, and inhibitors of IGFBP proteases. Therefore, assays based on IGF-related bioactivity may [...] Read more.
The bioactivity of the IGF system is not a function of isolated hormone concentrations in a given biological matrix. Instead, the biological activities of IGFs are regulated by IGFBPs, IGFBP proteases, and inhibitors of IGFBP proteases. Therefore, assays based on IGF-related bioactivity may describe functions of the complete IGF system in a given biological matrix. Of particular interest are the IGF system effects on the AKT/mTOR pathway, as a dominant system for controlling growth, metabolism, and aging. In order to improve the sensitivity of IGF-dependent bioactivity, we made use of the known short-term and enhancing effects of IGFBP2 on the intracellular PI3K pathway. As a specific readout of this pathway, and further as a marker of the mTOR pathway, we assessed the phosphorylation of AKT-Ser473. Preincubation using IGFBP2 enhanced IGF1-dependent AKT-Ser473 phosphorylation in our experimental system. The assay’s specificity was demonstrated by inhibition of IGF1 receptors outside or inside the cell, using antiserum or small molecule inhibitors, which reduced AKT phosphorylation in response to exogenous IGF1 (p < 0.05). The maximal response of AKT phosphorylation was recorded 15 to 60 min after the addition of IGF1 to cell monolayers (p < 0.001). In our cellular system, insulin induced AKT phosphorylation only at supra-physiological concentrations (µM). Using this novel assay, we identified the differential biological activity of the IGF system in AKT-Ser473 phosphorylation in serum (mouse, naked mole rat, and human), in cerebrospinal fluid (human), and in colostrum or mature milk samples (dairy cow). We have developed a sensitive and robust bioassay to assess the IGF-related activation of the AKT/mTOR pathway. The assay works efficiently and does not require expensive cell culture systems. By using capillary immuno-electrophoresis, the readout of IGF-related bioactivity is substantially accelerated, requiring a minimum of hands-on time. Importantly, the assay system is useful for studying IGF-related activity in the AKT/mTOR pathway in a broad range of biological matrices. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Insulin-like growth factor-1 production by neonatal mouse cardiac fibroblasts in response to growth hormone is defective and dispensable for hypertrophy of neonatal mouse cardiomyocytes
Authors: Pietro Ameri
Affiliation: Dipartimento di medicina interna e specialità mediche - DIMI Università di Genova
Abstract: Introduction: Growth hormone (GH) causes cardiac hypertrophy, which, in principle, may be secondary to direct action of GH on cardiomyocytes or to the effects of insulin-like growth factor 1 (IGF-1) released by non-cardiomyocytes upon GH stimulation. Nonetheless, the relative contribution of GH vs paracrine IGF-1 in GH-elicited cardiomyocyte hypertrophy remains unclear. Objectives: We investigated the role that the GH-IGF-1 axis plays in cardiomyocyte hypertrophy. Materials & methods: cFib and cardiomyocytes were isolated from the hearts of 1-2 day-old C57BL6/J mice. For comparative experiments, cFib obtained from the hearts of Wistar rat pups and the mouse 3T3 embryonic fibroblast cell line were also used. Cells were incubated with recombinant human GH, which is known to act through both mouse and rat GH receptor (GHR), for 48 hours. Gene and protein expression was evaluated by targeted or array RT-PCR, western blotting, and/or immunofluorescence. Concentrations of IGF-1 in serum-free conditioned medium (CM) were measured by ELISA. The levels of hypertrophy genes and the phosphorylation of 4E-BP1, which leads to protein translation, were assessed by RT-PCR and western blotting, respectively, in cardiomyocytes treated for 24 hours with cFib or 3T3 CM. Results: Exogenous GH induced Igf1 and its targets in mouse, but not rat cFib. Several genes encoding components and modulators of the GH/GHR signaling pathway were also differentially expressed in the 2 cell populations following exposure to GH. Similar differences were found when mouse cFib and 3T3 cells were compared. Furthermore, protein expression of GHR and SOCS2, a negative regulator of GHR, was lower and higher, respectively, in mouse cFib as compared with 3T3 cells. Consistently, IGF-1 concentration in the CM increased when 3T3 Fib, but not mouse cFib, were incubated with GH, although it was higher in the latter than in the former in resting conditions. The CM of both mouse cFib and 3T3 cells stimulated the expression of the hypertrophy genes, Nppa and Nppb, in cardiomyocytes regardless of whether fibroblasts had previously been treated with GH or vehicle. Phosphorylation of 4E-BP1 was not enhanced either by the CM of GH- vs vehicle-treated mouse cFib. Conclusions: These data suggest that IGF-1 production by neonatal mouse cFib in response to GH is defective, possibly due to decreased levels of GHR, SOCS2 overexpression, and/or high baseline IGF-1 synthesis. However, IGF-1 is dispensable for the mouse cFib secretome to initiate hypertrophy of neonatal mouse cardiomyocytes. The study of cardiac IGF-1 actions in vitro is critically dependent on the used cell type.

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