Insulin-like Growth Factor Signaling Pathway Research Articles

Sex differences and heritability of adrenal steroidogenesis in offspring rats induced by prenatal nicotine exposure

The epidemiological investigation has suggested prenatal nicotine exposure (PNE) induces multiorgan developmental toxicity and increases the risk of metabolic diseases in offspring. Our previous study found that the occurrence of fetal-originated diseases was associated with abnormal adrenal development in offspring. However, the long-term harmful effects on adrenal development in offspring induced by PNE remain unclear. Pregnant Wistar rats were injected subcutaneously with nicotine (2 mg/kg·d) from gestation day (GD) 9 to GD20 to obtain the adrenal gland from fetal and adult offspring rats of F1 and F2 generations. We found that the adrenal insulin-like growth factor 1 (IGF1) signaling pathway and steroidogenic function were increased in male while decreased in female of PNE fetal rats, which could extend into adulthood. Furthermore, the primary adrenal cells of fetal rats were treated with nicotine to observe the phenomena and clarify the possible mechanism of the sex difference. The results suggested that there are sex differences in IGF1 signaling pathway and steroidogenic function induced by PNE, which may be associated with sex differences in nAChRβ1 expression. In addition, the adrenal steroidogenic function was reduced in F2 offspring of F1 PNE female rats (regardless of mating with control or Male PNE rats). Therefore, the decrease of adrenal steroidogenic function in female offspring rats induced by PNE has maternal heritability. In conclusion, PNE could lead to sex differences and heritability of adrenal steroidogenic function in offspring rats.

Decoding Insulin-Like Growth Factor Signaling Pathway From a Non-coding RNAs Perspective: A Step Towards Precision Oncology in Breast Cancer.

Breast cancer (BC) is a highly complex and heterogenous disease. Several oncogenic signaling pathways drive BC oncogenic activity, thus hindering scientists to unravel the exact molecular pathogenesis of such multifaceted disease. This highlights the urgent need to find a key regulator that tunes up such intertwined oncogenic drivers to trim the malignant transformation process within the breast tissue. The Insulin-like growth factor (IGF) signaling pathway is a tenacious axis that is heavily intertwined with BC where it modulates the amplitude and activity of vital downstream oncogenic signaling pathways. Yet, the complexity of the pathway and the interactions driven by its different members seem to aggravate its oncogenicity and hinder its target-ability. In this review, the authors shed the light on the stubbornness of the IGF signaling pathway and its potential regulation by non-coding RNAs in different BC subtypes. Nonetheless, this review also spots light on the possible transport systems available for efficient delivery of non-coding RNAs to their respective targets to reach a personalized treatment code for BC patients.

IGF Signaling in Intervertebral Disc Health and Disease

Low back pain (LBP) is a common musculoskeletal symptom, which brings a lot of pain and economic loss to patients. One of the most common causes of LBP is intervertebral disc degeneration (IVDD). However, pathogenesis is still debated, and therapeutic options are limited. Insulin-like growth factor (IGF) signaling pathways play an important role in regulating different cell processes, including proliferation, differentiation, migration, or cell death, which are critical to the homeostasis of tissues and organs. The IGF signaling is crucial in the occurrence and progression of IVDD. The activation of IGF signaling retards IVDD by increasing cell proliferation, promoting extracellular matrix (ECM) synthesis, inhibiting ECM decomposition, and preventing apoptosis and senescence of disc cells. However, abnormal activation of IGF signaling may promote the process of IVDD. IGF signaling is currently considered to have a promising treatment prospect for IVDD. An in-depth understanding of the role of IGF signaling in IVDD may help find a novel approach for IVDD treatment.

Effect of vanillic acid on pentylenetetrazole-kindled rats: Nrf2/HO-1, IGF-1 signaling pathways cross talk.

Vanillic acid (VA) exhibited antioxidant and neuroprotective properties in some neurodegenerative disorders. So, the current study examined the neuroprotective potential of VA as an antiepileptic agent in pentylenetetrazole (PTZ)-induced epileptic rats and the prospective role of Insulin like growth factor-1 (IGF-1) and nuclear factor-2 erythroid-related factor-2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in this respect. Thirty male albino rats were equally subdivided into 3 groups; (1) normal control (NC) group, (2) PTZ-group: received PTZ (50 mg/Kg, i.p. every other day) for 14 days, and (3) PTZ + VA group: received PTZ and VA (50 mg/Kg daily for 2 weeks). The seizure score and latency were evaluated after PTZ injection. Also, the markers of oxidative stress (malondialdehyde (MDA), catalase, and reduced glutathione (GSH)), histopathological examination, the expression of glial fibrillary acidic protein (GFAP) (a marker of astrocytes) IGF-1, Nrf2, and HO-1 were assessed in the brain tissues by the end of the experiment. PTZ caused significant decrease in seizure latency and significant increase in seizure score by the end of the experiment (p < 0.01). This was associated with significant increase in MDA and GFAP with significant decrease in GSH, total antioxidant capacity (TAC) and IGF-1 in brain tissues compared to normal group (p < 0.01). On the other hand, treatment with VA caused significant attenuation in PTZ-induced seizures which was associated with significant improvement in oxidative stress markers and downregulation in GFAP and upregulation of Nrf2, HO-1 and IGF-1 in CA3 hippocampal region (p < 0.01). VA showed neuroprotective and anti-epileptic effects against PTZ-induced epilepsy which probably might be due to its antioxidant properties and upregulation of Nrf2/HO-1 pathway and IGF-1.

Association of insulin-like growth factor binding protein-7 promoter methylation with esophageal cancer in peripheral blood.

The insulin-like growth factor (IGF) signaling pathway has an important role in many cancers, including esophageal cancer (EC). IGF-binding protein 7 (IGFBP7) is one of the proteins in this signaling pathway, and its role in cancer has not yet been fully clarified. In the present study, we evaluated the clinical relevance of IGFBP7 methylation status and mRNA expression in EC patients compared to healthy controls. We also investigated whether IGFBP7 methylation status affects mRNA expression. The study comprised 100 EC patients and 105 healthy controls. Methylation specific PCR (MSP) was used to examine IGFBP7's promoter methylation and real-time quantitative reverse transcription PCR (qRT-PCR) was used to assess IGFBP7 mRNA expression. The IGFBP7 promoter methylation was significantly higher in controls than in EC patients (p < 0.05). IGFBP7 mRNA expression was significantly lower in EC patients compared to controls, especially in those over 55years old (p < 0.0001). The globulin level and reflux were significantly higher in IGFBP7-unmethylated patients compared to IGFBP7 methylated patients (p = 0.01). In EC patients, however, there was no significant relationship between IGFBP7 mRNA expression and methylation in the peripheral blood (p = 0.33). In addition, neither IGFBP7 mRNA expression nor methylation were shown to be linked with survival (p > 0.05). Our study indicated that promoter unmethylation and mRNA expression of the IGFBP7 promoter in peripheral blood could be different biomarkers for EC. Furthermore, unmethylation of the IGFBP7 promoter in EC patients was associated with reflux and elevated globulin levels. More studies with a larger number of cases is needed to confirm this association.

Microbiome mediation of animal life histories via metabolites and insulin-like signalling.

The regulatory pathways by which gut microbiota potentially shape host life histories remain largely untested, however, a constellation of research suggests that gut bacteria likely have significant effects on their hosts via metabolites. In this article we review known and hypothesized pathways by which gut microbiota influence host life histories through interfacing with the neuroendocrine system, with a focus on the insulin-like growth factor (IGF) signalling pathway. Bacterially derived metabolites including short-chain fatty acids (SCFAs), polyamines, and peptides likely impact host life histories as metabolic substrates, essential nutrients, and via molecular signalling with well-studied neuroendocrine pathways. The hypothalamus-pituitary axis and insulin-like signalling (ILS) pathways are central regulatory networks for development, growth, reproductive maturity, reproduction, and senescence and are likely targets for tests of how gut bacterial metabolites shape host life histories. SCFAs in particular, as metabolites derived from bacterial fermentation, are implicated as significant microbiome signalling molecules shown to interface with the ILS pathway as well as to bind to receptors on neuroendocrine and peripheral nervous tissues. For example, experimental increases of SCFA production have been shown to affect IGF-1 levels in circulation and are associated with robust development, growth, reproduction, and delayed senescence. Finally, emerging -omics approaches are providing integrative ways to test and detail the potential diverse ways in which gut microbiota interact with their hosts and the likely important roles they play in shaping host life-history responses to varied environmental conditions.

Antenatal dexamethasone retarded fetal long bones growth and development by down-regulating of insulin-like growth factor 1 signaling in fetal rats.

Dexamethasone (DEX), a synthetic glucocorticoid, has been widely used as a medication for premature delivery. However, the side effects of antenatal DEX treatment on fetal bone development, as well as the underlying mechanisms still remain to be elucidated. Here, we aimed to explore the effects and the related mechanisms of antenatal DEX exposure during late pregnancy on fetal bone growth and development. Pregnant Sprague-Dawley rats were randomly divided into DEX group and vehicle group from gestational day 14 (GD14). Pregnant rats in DEX group were intraperitoneally injected once with DEX (200µg/kg body weight) on GD14, 16, 18, and 20. The vehicle group rats were administered the same amount of normal saline at the same time. Pregnant rats were anesthetized at GD21 to harvest fetal femurs for analysis. Antenatal DEX treatment delayed fetal skeletal growth via inhibiting extracellular matrix (ECM) synthesis and downregulating insulin-like growth factor 1 (IGF1) signaling. Several components of IGF1 signaling pathway, including IGF1 receptor, insulin receptor substrate, as well as serine-threonine protein kinase, were down-regulated in fetal growth plate chondrocytes following DEX treatment. This study indicated that antenatal DEX treatment-retarded fetal skeletal growth was associated with the down-regulation of IGF1 signaling in growth plate chondrocytes, providing important information about the impact of antenatal DEX application four courses on premature infant.

The Insulin-like Growth Factor Signalling Pathway in Cardiac Development and Regeneration.

Insulin and Insulin-like growth factors (IGFs) perform key roles during embryonic development, regulating processes of cell proliferation and survival. The IGF signalling pathway comprises two IGFs (IGF1, IGF2), two IGF receptors (IGFR1, IGFR2), and six IGF binding proteins (IGFBPs) that regulate IGF transport and availability. The IGF signalling pathway is essential for cardiac development. IGF2 is the primary mitogen inducing ventricular cardiomyocyte proliferation and morphogenesis of the compact myocardial wall. Conditional deletion of the Igf1r and the insulin receptor (Insr) genes in the myocardium results in decreased cardiomyocyte proliferation and ventricular wall hypoplasia. The significance of the IGF signalling pathway during embryonic development has led to consider it as a candidate for adult cardiac repair and regeneration. In fact, paracrine IGF2 plays a key role in the transient regenerative ability of the newborn mouse heart. We aimed to review the current knowledge about the role played by the IGF signalling pathway during cardiac development and also the clinical potential of recapitulating this developmental axis in regeneration of the adult heart.

Expression Profiles and Prognostic Value of FABPs in Colorectal Adenocarcinomas.

Colorectal cancer (CRC) is one of the world’s leading causes of cancer-related deaths; thus, it is important to detect it as early as possible. Obesity is thought to be linked to a large rise in the CRC incidence as a result of bad dietary choices, such as a high intake of animal fats. Fatty acid-binding proteins (FABPs) are a set of molecules that coordinate intracellular lipid responses and are highly associated with metabolism and inflammatory pathways. There are nine types of FABP genes that have been found in mammals, which are FABP1–7, FABP9, and FABP12. Each FABP gene has its own roles in different organs of the body; hence, each one has different expression levels in different cancers. The roles of FABP family genes in the development of CRC are still poorly understood. We used a bioinformatics approach to examine FABP family gene expression profiles using the Oncomine, GEPIA, PrognoScan, STRING, cBioPortal, MetaCore, and TIMER platforms. Results showed that the FABP6 messenger (m)RNA level is overexpressed in CRC cells compared to normal cells. The overexpression of FABP6 was found to be related to poor prognosis in CRC patients’ overall survival. The immunohistochemical results in the Human Protein Atlas showed that FABP1 and FABP6 exhibited strong staining in CRC tissues. An enrichment analysis showed that high expression of FABP6 was significantly correlated with the role of microRNAs in cell proliferation in the development of CRC through the insulin-like growth factor (IGF) signaling pathway. FABP6 functions as an intracellular bile-acid transporter in the ileal epithelium. We looked at FABP6 expression in CRC since bile acids are important in the carcinogenesis of CRC. In conclusion, high FABP6 expression is expected to be a potential biomarker for detecting CRC at the early stage.

Regulation of the IGF1 signaling pathway is involved in idiopathic pulmonary fibrosis induced by alveolar epithelial cell senescence and core fucosylation.

Idiopathic pulmonary fibrosis (IPF) mainly occurs in elderly people over the age of sixty. IPF pathogenesis is associated with alveolar epithelial cells (AECs) senescence. Activation of PI3K/AKT signaling induced by insulin-like growth factor 1 (IGF1) participates in AEC senescence and IPF by releasing CTGF, TGF-β1, and MMP9. Our previous study demonstrated that core fucosylation (CF) modification, catalyzed by a specific core fucosyltransferase (FUT8) can regulate the activation of multiple signaling pathways, and inhibiting CF can alleviate pulmonary fibrosis in mice induced by bleomycin. However, whether CF is involved in IGF1-mediated AEC senescence in IPF remains unclear. In this study, we found that the IGF1/PI3K/AKT signaling pathway was activated in IPF lung tissue. Meanwhile, CF was present in senescent AECs. We also showed that IGF1 could induce AECs senescence with enhanced CF in vivo and in vitro. Inhibiting CF alleviated AECs senescence and pulmonary fibrosis induced by IGF1. In addition, activation of IGF1/PI3K/AKT signaling depends on CF. In conclusion, this study confirmed that CF is an important target regulating the IGF1 signaling pathway in AEC senescence and IPF, which might be a candidate target to treat IPF in the future.

The IGF-1 Signaling Pathway in Viral Infections.

Insulin-like growth factor-1 (IGF-1) and the IGF-1 receptor (IGF-1R) belong to the insulin-like growth factor family, and IGF-1 activates intracellular signaling pathways by binding specifically to IGF-1R. The interaction between IGF-1 and IGF-1R transmits a signal through a number of intracellular substrates, including the insulin receptor substrate (IRS) and the Src homology collagen (Shc) proteins, which activate two major intracellular signaling pathways: the phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways, specifically the extracellular signal-regulated kinase (ERK) pathways. The PI3K/AKT kinase pathway regulates a variety of cellular processes, including cell proliferation and apoptosis. IGF1/IGF-1R signaling also promotes cell differentiation and proliferation via the Ras/MAPK pathway. Moreover, upon IGF-1R activation of the IRS and Shc adaptor proteins, Shc stimulates Raf through the GTPase Ras to activate the MAPKs ERK1 and ERK2, phosphorylate and several other proteins, and to stimulate cell proliferation. The IGF-1 signaling pathway is required for certain viral effects in oncogenic progression and may be induced as an effect of viral infection. The mechanisms of IGF signaling in animal viral infections need to be clarified, mainly because they are involved in multifactorial signaling pathways. The aim of this review is to summarize the current data obtained from virological studies and to increase our understanding of the complex role of the IGF-1 signaling axis in animal virus infections.

Chemotherapy-induced peripheral neuropathy is promoted by enhanced spinal insulin-like growth factor-1 levels via astrocyte-dependent mechanisms

BackgroundChemotherapy-induced peripheral neuropathy (CIPN) is a common and intractable complication in chemotherapy-receiving patients. Insulin-like growth factor-1 (IGF-1) is a popular neurotrophin with various functions, such as maintaining neuronal survival and synaptic functioning in the central nervous system. Therefore, we hypothesized that the IGF-1 signaling pathway could be a candidate target for treating CIPN. MethodsWe established the CIPN model by injecting mice intraperitoneally with oxaliplatin and assessed IGF-1 protein expression, its receptor IGF1R, phospho-IGF1R (p-IGF1R), interleukin-17A (IL-17A), tumor necrosis factor-α (TNF-α), and calcitonin gene-related peptide (CGRP) in the lumbar spinal cord with Western blot and immunofluorescence. To examine the effect of IGF-1 signaling on CIPN, we injected mice intrathecally or intraperitoneally with mouse recombinant IGF-1 (rIGF-1). ResultsIGF-1 protein expression decreased significantly in the spinal cord on D3 and D10 (the 3rd and 10th days after beginning oxaliplatin chemotherapy) and was co-localized with astrocytes primarily in the lumbar spinal cord, whereas IGF1R was predominantly expressed on neurons. Both intrathecally- and intraperitoneally-administered rIGF-1 relieved the chemotherapy-induced pain-like behavior and reduced IL-17A, TNF-α, and CGRP protein expressions in the spinal cord. ConclusionOur results indicate a vital role for IGF-1 signaling in CIPN. Targeting IGF-1 signaling could be a potent therapeutic strategy for treating CIPN in clinical settings.

Insulin-like growth factor 1 gene transfer for sporadic Alzheimer's disease: New evidence for trophic factor mediated hippocampal neuronal and synaptic recovery-based behavior improvement.

Sporadic Alzheimer's disease (sAD) is the most prevalent neurodegenerative disorder with no cure. Patients typically suffer from cognitive impairment imprinted by irreversible neocortex and hippocampal degeneration with overt synaptic and neuron dysfunction. Insulin-like growth factor 1 (IGF1) has proven to be a potent neuroprotective molecule in animal models of age-related neurodegeneration. In this regard, adenoviral gene transfer aiming at IGF1 brain overexpression has been hitherto an underexplored approach for the sAD treatment. We postulated enhanced IGF1 signaling in the brain as a restorative means in the diseased brain to revert cognitive deficit and restore hippocampal function. We implemented recombinant adenovirus mediated intracerebroventricular IGF1 gene transfer on the streptozotocin (STZ) induced sAD rat model, using 3-month-old male Sprague Dawley rats. This approach enhanced IGF1 signaling in the hippocampus and dampened sAD phosphorylated Tau. We found a remarkable short-term improvement in species-typical behavior, recognition memory, spatial memory, and depressive-like behavior. Histological analysis revealed a significant recovery of immature hippocampal neurons. We additionally recorded an increase in hippocampal microglial cells, which we suggest to exert anti-inflammatory effects. Finally, we found decreased levels of pre- and postsynaptic proteins in the hippocampus of STZ animals. Interestingly, IGF1 gene transfer increased the levels of PSD95 and GAD65/67 synaptic markers, indicating that the treatment enhanced the synaptic plasticity. We conclude that exogenous activation of IGF1 signaling pathway, 1 week after intracerebroventricular STZ administration, protects hippocampal immature neurons, dampens phosphorylated Tau levels, improves synaptic function and therefore performs therapeutically on the sAD STZ model. Hence, this study provides strong evidence for the use of this trophic factor to treat AD and age-related neurodegeneration.

Insulin-Like Peptides and Cross-Talk With Other Factors in the Regulation of Insect Metabolism

The insulin-like peptide (ILP) and insulin-like growth factor (IGF) signalling pathways play a crucial role in the regulation of metabolism, growth and development, fecundity, stress resistance, and lifespan. ILPs are encoded by multigene families that are expressed in nervous and non-nervous organs, including the midgut, salivary glands, and fat body, in a tissue- and stage-specific manner. Thus, more multidirectional and more complex control of insect metabolism can occur. ILPs are not the only factors that regulate metabolism. ILPs interact in many cross-talk interactions of different factors, for example, hormones (peptide and nonpeptide), neurotransmitters and growth factors. These interactions are observed at different levels, and three interactions appear to be the most prominent/significant: (1) coinfluence of ILPs and other factors on the same target cells, (2) influence of ILPs on synthesis/secretion of other factors regulating metabolism, and (3) regulation of activity of cells producing/secreting ILPs by various factors. For example, brain insulin-producing cells co-express sulfakinins (SKs), which are cholecystokinin-like peptides, another key regulator of metabolism, and express receptors for tachykinin-related peptides, the next peptide hormones involved in the control of metabolism. It was also shown that ILPs in Drosophila melanogaster can directly and indirectly regulate AKH. This review presents an overview of the regulatory role of insulin-like peptides in insect metabolism and how these factors interact with other players involved in its regulation.

The Olfactory Receptor Gene Product, OR5H2, Modulates Endometrial Cancer Cells Proliferation via Interaction with the IGF1 Signaling Pathway.

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.

인슐린유사성장인자 신호전달이 참굴(Crassostrea gigas)의 비만도에 미치는 영향

Study on insulin-like growth factor-1 (IGF-1) which plays a role in regulating proliferation, differentiation, growth, and survival in vertebrates, has been reported mainly in fish and a correlation between IGF-1 activity and growth has been described in some bivalves. In Korea, the Pacific oyster Crassostrea gigas is an important species, and its growth and reproduction were dependent on the condition index (CI) and tissue weight rate (TWR). Therefore, we investigated effects of the expression of IGF-1 signal in mantle edge, gill, labial palp and digestive gland of C. gigas during about 1 year, using immunoblot analysis to assess the relationship between IGF-1 receptor (IGF-1R) activity and CI. The activation of the IGF-1 signaling pathway, including the IGF-1R ß-subunit, could be detected high in May when CI and TWR were high. IGF-1R was activated and regulated the downstream IGF-1 signaling in tissues of C. gigas. However, the level of each factors of IGF family expression was depended on tissues and month. These results suggest that the increased activation of IGF-1 signal could be related to the condition index of C. gigas.

Systemic effect of FHL1 on neuromuscular junction and myotube formation via insulin-like growth factor and myostatin signaling pathways

Four-and-a-half LIM domain protein 1 (FHL1) is a member of the FHL protein family that serves as a scaffold protein to maintain normal cellular structure and function. Its mutations have been implicated in multiple muscular diseases. These FHL1 related myopathies are characterized by symptoms such as progressive muscle loss, rigid or bent spine, even cardiac or respiratory failure in some patients, which implies pathological problems not only in muscles, but also in the nervous system. Moreover, decreased FHL1 protein level has been found in patients with FHL1 mutations, indicating the protein loss-of-function as a pathological cause of such diseases. These findings suggest the significance of understanding the systemic role of FHL1 in the homeostasis of nervous system and muscle. Here we reported that Fhl1 loss in C2C12 myotubes obscured acetylcholine receptor (AChR) clustering in addition to myotube fusion, which was associated with impaired MuSK phosphorylation. Mechanistically, myostatin-SMAD2/3 signaling was enhanced, whereas IGF-PI3K-AKT signaling was suppressed in Fhl1−/− C2C12 myotubes. Reversion of these molecular alterations rescued AChR clustering and differentiation deficits. These data outline a systemic regulation of AChR clustering and myotube fusion by FHL1, which may offer clues for mechanism study and development of therapeutic strategies to treat FHL1 related myopathies.

Effect of Lycopene on Oral Squamous Cell Carcinoma Cell Growth by Inhibiting IGF1 Pathway.

PurposeLycopene has produced robust clinical effects and shows a promising chemopreventive in the oral cancer and precancerous lesions. However, much is still unknown about its mechanisms of the carotenoid in protecting against oral squamous cell carcinoma (OSCC). Insulin-like growth factor 1 (IGF1) pathway serves as a key regulatory signal pathway in the tumor microenvironment, which may be associated with the angiogenesis, tumorigenicity, and cancer proliferation. The current study was focused on elucidating the potential pathway played for lycopene to exert its function in treating with OSCC.Materials and MethodsFirstly, we explored the dose- and time-response of CAL-27 and WSU-HN6 cells to lycopene. Both cells were incubated with various concentrations of lycopene (0.25, 0.5, 1, 2 µM). The inhibiting rate of cell proliferation was assessed using MTT assay. To observe the regulating effect of lycopene on OSCC, cell migration, apoptosis and tumor formation were detected in vitro and in vivo. The potential signaling pathways of OSCC cells treated with lycopene were analyzed by Affymetrix microarrays. And then, we investigated the changing of IGF1 signaling pathway, on the protein levels of tumor tissue after lycopene.ResultsCell proliferation was inhibited by lycopene in a dose- and time-dependent manner. The optimum inhibition efficiencies for OSCC cells were also found. Further, the results also demonstrated that pre-treatment of OSCC with lycopene drastically induced cell apoptosis suppresses cell migration and tumor growth. Mechanistically, ingenuity pathway analysis further revealed that IGF1 pathway participate in killing effects on OSCC after treatment of lycopene. Lycopene may inhibit the pathway by regulating protein expression of IGF1, IGF binding protein (BP) 1, IGFBP3, transcription factor Jun/AP-1 (JUN), and forkhead box O1 (FOXO1).ConclusionThese observations indicate that lycopene regulates OSCC cell growth by inhibiting IGF1 pathway, which may be a promising agent for the treatment of OSCC.

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

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.

Identification of nephronectin as a new target for IGF1 action.

The growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis has a key role in normal growth and development. Laron syndrome (LS) is a type of dwarfism that results from mutation of the GH receptor, leading to congenital IGF1 deficiency. Epidemiological studies have shown that LS patients are protected from cancer. Genome-wide profiling led to the identification of a series of metabolic genes whose differential expression in LS might be linked to cancer protection. Nephronectin (NPNT) is an intracellular and secreted extracellular matrix protein with important roles in kidney development. NPNT was identified as the top-downregulated gene in LS-derived cells in comparison with ethnic-, age- and gender-matched controls (p-value=0.0148; fold-change=-3.12 versus controls). NPNT has not been previously linked to the IGF1 signaling pathway. The present study was aimed at evaluating the hypothesis that NPNT is a new target for IGF1 action and that decreased expression of NPNT in LS is correlated with cancer protection. Basal and IGF1-stimulated NPNT expression were assessed in LS lymphoblastoid cells as well as in human breast and prostate cancer cells. NPNT silencing experiments were conducted using siRNA methodology. We provide evidence that IGF1 stimulates NPNT expression in LS-derived lymphoblastoids and various cancer cell lines. In addition, we demonstrate that NPNT silencing results in diminished activation of the AKT and ERK1/2 pathways, with ensuing decreases in cellular proliferation. Our data identified the NPNT gene as a target for IGF1 action. The clinical implications of the functional and physical interactions between NPNT and the IGF1 pathway merit further investigation.