Role Of Epidermal Growth Factor Research Articles

Pituitary Actions of EGF on Gonadotropins, Growth Hormone, Prolactin and Somatolactins in Grass Carp

Simple SummaryIn mammals, the functions of epidermal growth factor (EGF) have been widely studied. However, little is known about the pituitary actions of EGF in teleost. Using primary cultured grass carp pituitary cells as model, we found that EGF could reduce pituitary luteinizing hormone β (LHβ) mRNA expression, but induce pituitary growth hormone (GH), prolactin (PRL) and somatolactins (SL) mRNA expression. Furthermore, we also found that NKB could suppress EGF-induced PRL mRNA expression in grass carp pituitary cells. These results suggested that EGF could directly regulate pituitary hormones expression in teleost.In mammals, epidermal growth factor (EGF) plays a vital role in both pituitary physiology and pathology. However, the functional role of EGF in the regulation of pituitary hormones has rarely reported in teleost. In our study, using primary cultured grass carp pituitary cells as an in vitro model, we examined the effects of EGF on pituitary hormone secretion and gene expression as well as the post-receptor signaling mechanisms involved. Firstly, we found that EGF significantly reduced luteinizing hormone (LHβ) mRNA expression via ErbB1 coupled to ERK1/2 pathway, but had no effect on LH release in grass carp pituitary cells. Secondly, the results showed that EGF was effective in up-regulating mRNA expression of growth hormone (GH), somatolactin α (SLα) and somatolactin β (SLβ) via ErbB1 and ErbB2 and subsequently coupled to MEK1/2/ERK1/2 and PI3K/Akt/mTOR pathways, respectively. However, EGF was not effective in GH release in pituitary cells. Thirdly, we found that EGF strongly induced pituitary prolactin (PRL) release and mRNA expression, which was mediated by ErbB1 and subsequent stimulation of MEK1/2/ERK1/2 and PI3K/Akt/mTOR pathways. Interestingly, subsequent study further found that neurokinin B (NKB) significantly suppressed EGF-induced PRL mRNA expression, which was mediated by neurokinin receptor (NK2R) and coupled to AC/cAMP/PKA signal pathway. These results suggested that EGF could differently regulate the pituitary hormones expression in grass carp pituitary cells.

The Level of Epidermal Growth Factor and Its Relationship with Leukocytes and Mast Cells in Experimental Interstitial Cystitis / Painful Bladder Syndrome

Introduction. The causes and mechanisms of interstitial cystitis / painful bladder syndrome (IC / PBS) remain poorly understood. The pathogenesis and the etiology of the disease is still not clearly defined. Of great interest is the role of epidermal growth factor (EGF). Due to the complexity of the pathophysiology of IC / PBS, several animal models are used to better understand the mechanisms of this disease.Purpose of the study. to determine the level of epidermal growth factor (EGF) and its association with leukocytes and mast cells of the bladder tissue in animals with experimental models of interstitial cystitis / painful bladder syndrome.Materials and methods. IC / PBS modeling was carried out on 29 individuals of white New Zealand female rabbits, which were divided into 4 groups. EGFs were determined in blood and urine by ELISA. Cellular changes in tissues were assessed by histological method.Results. A high level of EGF in urine was detected in groups 1 and 2, exceeding the intact group by 33.3% (p <0.05) and 34.6% (p <0.05), respectively. In group 1, after 14 days, EGF decreased in blood by 16.2%, in urine - by 35.5% (p <0.05). In group 2, the level of EGF increased in blood (by 61.2%, p <0.01), in urine (by 28.7%). The greatest number of lymphocytes was detected in animals of the group 2 (p <0.001). Mast cells were determined only in groups 1 and 2, and in the latter their number was greater (p <0.001) than in group 1. A strong correlation was found between the value of EGF in the blood and mast cells, as well as between the level of EGF in the urine and eosinophils in group 1. In group 2, there was a direct weak relationship between the concentration of EGF in the urine and the number of lymphocytes and mast cellsConclusion. A statistically significant increase of EGF in blood and urine was obtained in animals with simulated IC / PBS by introducing urine into the wall of the bladder. This modeling option contributed to the activation of mast cells of the bladder tissue. The association of EGF with mast cells in IC / PBS was revealed. Changes in EGF levels may be associated with IC / PBS.The study did not have sponsorship. The authors have declared no conflicts of interest.

Plakophilin 3 phosphorylation by ribosomal S6 kinases supports desmosome assembly.

Desmosome remodeling is crucial for epidermal regeneration, differentiation and wound healing. It is mediated by adapting the composition, and by post-translational modifications, of constituent proteins. We have previously demonstrated in mouse suprabasal keratinocytes that plakophilin (PKP) 1 mediates strong adhesion, which is negatively regulated by insulin-like growth factor 1 (IGF1) signaling. The importance of PKP3 for epidermal adhesion is incompletely understood. Here, we identify a major role of epidermal growth factor (EGF), but not IGF1, signaling in PKP3 recruitment to the plasma membrane to facilitate desmosome assembly. We find that ribosomal S6 kinases (RSKs) associate with and phosphorylate PKP3, which promotes PKP3 association with desmosomes downstream of the EGF receptor. Knockdown of RSKs as well as mutation of an RSK phosphorylation site in PKP3 interfered with desmosome formation, maturation and adhesion. Our findings implicate a coordinate action of distinct growth factors in the control of adhesive properties of desmosomes through modulation of PKPs in a context-dependent manner.

More is Not Always Better in Hair Growth Factors. Epidermal Growth Factor: Hair Growth Factor Involved in Alopecia Areata Pathogenesis.

Background:Alopecia areata (AA) is the second most frequent nonscarring alopecia after androgenetic alopecia; the trigger factor induces changes in the growth plate of hair bulb and leads to premature termination of anagen phase. Epidermal growth factor (EGF) can be the key molecule that participates in initiation and suppression of normal hair growth cycle. The role of EGF in the pathogenesis of AA is still uncertain.Aim of the Work:This aim is to estimate the serum level of EGF in patients with AA trying to detect its role in AA pathogenesis and correlate it with the disease severity.Subjects and Methods:This case–control study included 60 clinically diagnosed patients with AA with different variants and severities and 25 age- and sex-matched healthy controls. EGF level was measured using ELISA.Results:The mean serum EGF was statistically significantly higher in patients than of controls (P < 0.0003). The EGF level was higher in patients with disease duration >1 month than patients with disease duration ≤ 1 month, and it was higher in patients with high recurrence than patients without recurrence (P > 0.05). The EGF in patients of severe AA was statistically significantly higher than moderate AA patients, and moderate cases were higher than mild AA patients (P = 0.0001). Furthermore, the level of EGF with scalp involvement was higher; the highest serum level of EGF marker in S4 (75%-99%) hair loss then S3 (50%-74% hair loss), illustrated in table (4) followed by different percentage of hair loss, difference statistically significant.Conclusions:Elevated hair-specific growth factor as EGF is not always a good sign for hair growth and functioning promotor inducing hair recovery, but it may be linked to the pathogenesis of hair disorders as AA.

The glycoproteins EDIL3 and MFGE8 regulate vesicle-mediated eggshell calcification in a new model for avian biomineralization

The avian eggshell is a critical physical barrier, which permits extra-uterine development of the embryo. Its formation involves the fastest known biomineralization process in vertebrates. The eggshell consists of proteins and proteoglycans that interact with the mineral phase to impart its specific microstructure and mechanical properties. In this study, we investigated the role of epidermal growth factor (EGF)-like repeats and discoidin-like domains 3 (EDIL3) and milk fat globule-EGF factor 8 (MFGE8), two glycoproteins that are consistently detected in eggshell proteomes. We verified their common evolutionary history and identified the timing of the duplication event giving rise to these two distinct proteins. Edil3/mfge8 chromosomal locations revealed a nested syntenous relationship with other genes (hapln1/hapln3 and vcan/acan) that are also involved in vertebrate calcification. EDIL3 and MFGE8 proteins possess EGF-like and coagulation factor 5/8 (F5/8C) domains, and their 3D structures predicted that they bind calcium and extracellular vesicles. In chicken, we confirmed the presence of EDIL3 and MFGE8 proteins in eggshell, uterine fluid, and uterus. We observed that only edil3 is overexpressed in tissues in which eggshell mineralization takes place and that this overexpression occurs only at the onset of shell calcification. We therefore propose a model in which EDIL3 and, to a lesser extent, MFGE8 proteins guide vesicles containing amorphous calcium carbonate to the mineralization site. This model was supported by the observation that extracellular vesicles accumulate in uterine fluid during eggshell calcification and that they contain high levels of calcium, carbon, and oxygen that correspond to calcium carbonate.

Inhibition of epidermal growth factor receptor stimulates prolactin expression in primary culture of the mouse pituitary gland.

The roles of epidermal growth factor (EGF) in the regulation of prolactin (PRL) gene expression in the normal pituitary gland remain poorly understood. In the present study, the effects of EGF and an inhibitor of the EGF receptor, erlotinib, on PRL gene expression were examined both in the pituitary tumour cell line GH3 and in a primary culture of the mouse pituitary gland under similar experimental conditions. The results showed that EGF stimulated PRL expression in GH3 cells, but not in normal cells. Erlotinib was found to counteract EGF in GH3 cells inhibiting the PRL expression enhanced by EGF. By contrast, erlotinib induced an elevation in the PRL mRNA levels in the primary culture of the adult pituitary gland and the initiation of PRL production in the culture of the foetal pituitary gland in which PRL production had not yet occurred. Western blot analyses showed that EGF induced and erlotinib inhibited the activation of extracellular regulated protein kinase equally in GH3 and normal cells. These results suggest that the consequences of EGF receptor activation in normal PRL cells contradict those in adenomatous PRL cells.

Human Submandibular Salivary Gland Morphology Associated to Transcription and Growth Factors from Fetus to Aging

Saliva carries out several functions in the digestive system like the protection of the oral cavity and the beginning of carbohydrate digestion. This liquid is mainly produced by the submandibular gland as it is responsible for 60% of total saliva flow. This gland is characterized as acinar tubule composed, and during the fetal period, it develops in five stages, which are molded through high proliferative indices of the components. However, the aging process changes the morphology and function of this gland.Transcription factors such as Nanog and Signal transducer and activator of transcription 3 (Stat‐3) regulate the process of proliferation, ckit and musashi‐1 induce cell proliferation while epidermal growth factor (EGF) is secreted by the submandibular gland and it has combined action to the Stat‐3. Considering the importance of these transcription factors and the role of EGF, the present study evaluated immunohistochemical expression of EGF, Nanog, Ckit, Musashi‐1 and Stat‐3 in submandibular glands of human fetuses between 12 and 18 gestational weeks, in adults (40 to 55 years old) and senile (over 85 years old). It was also evaluated quantitatively the morphological changes in components during development using Image J and statistical softwares. This study was approved by the Research Ethical Committee of UNIFESP, research number 618131.The present study showed significant expression of all the transcription factors in the acinar system as in the ductal system during the stages of development. Also showed differences in the number of components between the adult and senile glands. Considering these results, we reinforce that the morphological changes observed in the submandibular gland is in consonance with the levels of the studied markers and the proliferation pattern during aging.Support or Funding InformationThis study was financed in part by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior ‐ Brasil (CAPES) Finance code 001 and also by FAPESP process number 2015/03967‐5.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The relation between serum levels of epidermal growth factor and necrotizing enterocolitis in preterm neonates.

PurposeNecrotizing enterocolitis (NEC) is one of the most serious complications of prematurity. Many risk factors can contribute to the development of NEC. The epidermal growth factor (EGF) plays a major role in intestinal barrier function, increases intestinal enzyme activity, and improves nutrient transport. The aim of this study was to assess the role of epidermal growth factor in the development of NEC in preterm neonates.MethodsIn this study, 130 preterm neonates were included and divided into 3 groups, as follows: group 1, 40 preterm neonates with NEC; group 2, 50 preterm neonates with sepsis; and group 3, 40 healthy preterm neonates as controls. The NEC group was then subdivided into medical and surgical NEC subgroups. The serum EGF level was measured using enzyme-linked immunosorbent assay.ResultsSerum EGF levels (pg/dL) were significantly lower in the NEC group (median [interquartile range, IQR], 9.6 [2–14]) than in the sepsis (10.1 [8–14]) and control groups (11.2 [8–14], P<0.001), with no significant difference between the sepsis and control groups, and were positively correlated with gestational age (r=0.7, P<0.001). A binary logistic regression test revealed that low EGF levels and gestational ages could significantly predict the development of NEC. The receiver-operating characteristic curve for EGF showed an optimal cutoff value of 8 pg/mL, with 73.3% sensitivity, 98% specificity, and an area under the curve of 0.92.ConclusionThe patients with NEC in this study had significantly lower serum EGF levels (P<0.001), which indicated that EGF could be a reliable marker of NEC in preterm neonates.

Transcriptomic and ChIP-sequence interrogation of EGFR signaling in HER2+ breast cancer cells reveals a dynamic chromatin landscape and S100 genes as targets

BackgroundThe Human Epidermal Growth Factor Receptor (EGFR/HER1) can be activated by several ligands including Transforming Growth Factor alpha (TGF-α) and Epidermal Growth Factor (EGF). Following ligand binding, EGFR heterodimerizes with other HER family members, such as HER2 (human epidermal growth factor receptor-2). Previously, we showed that the EGFR is upregulated in trastuzumab resistant HER2 positive (HER2+) breast cancer cells. This study is aimed to determine the downstream effects on transcription following EGFR upregulation in HER2+ breast cancer cells.MethodsRNA-sequence and ChIP-sequence for H3K18ac and H3K27ac (Histone H3 lysine K18 and K27 acetylation) were conducted following an Epidermal Growth Factor (EGF) treatment time course in HER2+ breast cancer cells, SKBR3. The levels of several proteins of interest were confirmed by western blot analysis. The cellular localization of proteins of interest was examined using biochemically fractionated lysates followed by western blot analysis.ResultsOver the course of 24 h, EGFR stimulation resulted in the modulation of over 4000 transcripts. Moreover, our data demonstrates that EGFR/HER2 signaling regulates the epigenome, with global H3K18ac and H3K27ac oscillating as a function of time following EGF treatment. RNA-sequence data demonstrates the activation of immediate early genes (IEGs) and delayed early genes (DEGs) within 1 h of EGF treatment. More importantly, we have identified members of the S100 (S100 Calcium Binding Protein) gene family as likely direct targets of EGFR signaling as H3K18ac, H3K27ac and pol2 (RNA polymerase II) increase near the transcription start sites of some of these genes.ConclusionsOur data suggests that S100 proteins, which act as Ca2+ sensors, could play a role in EGF induced tumor cell growth and metastasis, contribute to trastuzumab resistance and cell migration and that they are likely drug targets in HER2+ breast cancer.

Role of Epidermal Growth Factor in Oral Lichen Planus

Role of Epidermal Growth Factor in Oral Lichen Planus

Abstract 242: Large pathway and gene set analysis of GWAS data identifies novel associations for pancreatic cancer

Abstract Objective Genome-wide association studies (GWAS) identify associations of individual SNPs with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants has been shown for many disorders to be a powerful tool in discovering novel networks of susceptibility genes. Design We have conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product (sARTP) method to identify novel gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDA) in 9,040 cases and 12,495 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes identified in PDA-associated gene sets and pathways. Results We identified 14 gene sets and pathways associated with PDA at FDR &amp;lt; 0.05. Five of the strongest signals (P-value ≤ 1.3x10-5 Bonferroni corrected) were in genes from KEGG maturity onset diabetes of the young, Reactome regulation of beta cell development, Biocarta role of epidermal growth factor (EGF) receptor transactivation by G-protein-coupled receptors in cardiac hypertrophy pathway, Nikolsky breast cancer chr17q11-q21 amplicon gene set, and Pujana ATM Pearson correlation coefficient (PCC) network gene set. We identified and validated rs876493 and three correlated SNPs (PGAP3) and rs3124737 (CASP7) as eQTLs in two normal derived pancreas tissue datasets. Conclusion Our agnostic gene set and pathway analysis integrated with functional annotation and eQTL analysis provides novel insight into genes and pathways that may be biologically relevant for risk of PDA. Citation Format: Naomi Walsh, Han Zhang, Paula L. Hyland, Qi Yang, Evelina Mocci, Mingfeng Zhang, Erica J. Childs, Zhaoming Wang, Stephen Chanock, Patricia Hartge, Robert Hoover, Peter Kraft, Donghui Li, Eric J. Jacobs, Gloria M. Petersen, Brian M. Wolpin, Harvey A. Risch, Laufey T. Amundadottir, Kai Yu, Alison P. Klein, Rachael Z. Stolzenberg-Solomon. Large pathway and gene set analysis of GWAS data identifies novel associations for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 242.

Validation of EGFL6 expression as a prognostic marker in patients with lung adenocarcinoma in Taiwan: a retrospective study

ObjectiveLung adenocarcinoma is a non-small cell lung cancer, a common cancer in both genders, and has poor clinical outcome. Our aim was to evaluate the role of epidermal growth factor...

Apelin-induced cardioprotection against ischaemia/reperfusion injury: roles of epidermal growth factor and Src.

Apelin, the ligand of the G-protein-coupled receptor (GPCR) APJ, exerts a post-conditioning-like protection against ischaemia/reperfusion injury through activation of PI3K-Akt-NO signalling. The pathway connecting APJ to PI3K is still unknown. As other GPCR ligands act through transactivation of epidermal growth factor receptor (EGFR) via a matrix metalloproteinase (MMP) or Src kinase, we investigated whether EGFR transactivation is involved in the following three features of apelin-induced cardioprotection: limitation of infarct size, suppression of contracture and improvement of post-ischaemic contractile recovery. Isolated rat hearts underwent 30min of global ischaemia and 2h of reperfusion. Apelin (0.5μm) was infused during the first 20min of reperfusion. EGFR, MMP or Src was inhibited to study the pathway connecting APJ to PI3K. Key components of RISK pathway, namely PI3K, guanylyl cyclase or mitochondrial K+ -ATP channels, were also inhibited. Apelin-induced EGFR and phosphatase and tensing homolog (PTEN) phosphorylation were assessed. Left ventricular pressure and infarct size were measured. Apelin-induced reductions in infarct size and myocardial contracture were prevented by the inhibition of EGFR, Src, MMP or RISK pathway. The involvement of EGFR was confirmed by its phosphorylation. However, neither direct EGFR nor MMP inhibition affected apelin-induced improvement of early post-ischaemic contractile recovery, which was suppressed by Src and RISK inhibitors only. Apelin also increased PTEN phosphorylation, which was removed by Src inhibition. While EGFR and MMP limit infarct size and contracture, Src or RISK pathway inhibition suppresses the three features of cardioprotection. Src does not only transactivate EGFR, but also inhibits PTEN by phosphorylation thus playing a crucial role in apelin-induced cardioprotection.

Role of EGF on in situ culture of equine preantral follicles and metabolomics profile

The effects of epidermal growth factor (EGF) concentrations (0, 10, 50, and 100ng/ml) on in vitro culture (IVC) of equine preantral follicles were evaluated using histology, estradiol and reactive oxygen species (ROS) production and metabolomics. After IVC, the percentage of normal follicles was lower (P<0.05) for all treatments when compared to non-cultured control. EGF 50ng/ml treatment had more (P<0.05) normal follicles at Day 7 of culture when compared with EGF 0 and 100ng/ml. EGF 50ng/ml had more (P<0.05) developing follicles than the 0ng/ml and 10ng/ml EGF treatments. Follicular and oocyte diameters were greater (P<0.05) with EGF 50ng/ml than the other cultured treatments, but similar (P>0.05) to the non-cultured control. From Day 1 to Day 7 estradiol production increased (P<0.05) in all EGF treatments. EGF 50ng/ml was the only treatment that maintained ROS production through IVC. Metabolomics profiles of the spent media indicated that eleven ions from variable influence in the projection (VIP) scores were higher represented in the EGF 50ng/ml treatment. In conclusion, EGF 50ng/ml treatment maintained follicle survival and ROS production, and promoted activation of cultured equine preantral follicles enclosed in ovarian tissue.

Epidermal growth factor receptor (EGFR) involvement in successful growth hormone (GH) signaling in GH transduction defect

Growth hormone (GH) transduction defect (GHTD) is a growth disorder with impaired signal transducer and activator of transcription 3 (STAT3) phosphorylation mediated by overexpression of cytokine-inducible SH2-containing protein (CIS), which causes increased growth hormone receptor (GHR) degradation. This study investigated the role of epidermal growth factor (EGF) in the restoration of normal GH signaling in GHTD. Protein expression, cellular localization and physical contact of proteins of the GH and EGF signaling pathways were studied by Western immunoblotting, immunofluorescence and co-immunoprecipitation, respectively. These were performed in fibroblasts of one GHTD patient (P) and one control child (C) at the basal state and after induction with human GH (hGH) 200 μg/L (GH200), either with or without silencing of CIS mRNA, and after induction with hGH 1000 μg/L (GH1000) or 50 ng/mL EGF. The membrane availability of the EGF receptor (EGFR) and the activated EGFR (pEGFR) was increased in P only after simultaneous GH200 and silencing of CIS mRNA or with GH1000, whereas this occurred in C after GH200 alone. After EGF induction, the membrane localization of GHR, STAT3 and that of EGFR were increased in P more than in C. In conclusion, in GHTD, the EGFR seems to participate in successful GH signaling, but induction of GHTD fibroblasts with a higher dose of hGH is needed. The EGF/EGFR pathway, in contrast to the GH/GHR pathway, seems to function normally in P and is more primed compared to C. The involvement of the EGFR in successful GH signaling may explain the catch-up growth seen in the Ps when exogenous hGH is administered.

EGF induces epithelial-mesenchymal transition and cancer stem-like cell properties in human oral cancer cells via promoting Warburg effect.

“Warburg effect”, the enhanced glycolysis or aerobic glycolysis, confers cancer cells the ability to survive and proliferate even under stressed conditions. In this study, we explored the role of epidermal growth factor (EGF) in orchestrating Warburg effect, the epithelial-mesenchymal transition (EMT) process, and the acquisition of cancer stem-like cell properties in human oral squamous cell carcinoma (OSCC) cells. Our results showed that EGF induces EMT process in OSCC cells, which correlates with the acquisition of cancer stem-like properties, including the enrichment of CD44+/CD24− population of cancer cells and an increased expression of CSC-related genes, aldehyde dehydrogenase-1 (ALDH1) and Bmi-1. We also showed that EGF concomitantly enhanced L-lactate production, while blocking glycolysis by 2-deoxy-D-glucose (2-DG) robustly reversed EGF-induced EMT process and CSC-like properties in OSCC cells. Mechanistically, we demonstrated that EGF promoted EMT process and CSC generation through EGFR/PI3K/HIF-1α axis-orchestrated glycolysis. Using an orthotopic tumor model of human OSCC (UM-SCC1) injected in the tongue of BALB/c nude mice, we showed that treatment with 2-DG in vivo significantly inhibited the metastasis of tumor cells to the regional cervical lymph nodes and reduced the expression of ALDH1 and vimentin in both in situ tumors and tumor cell-invaded regional lymph nodes. Taken together, these findings have unveiled a new mechanism that EGF drives OSCC metastasis through induction of EMT process and CSC generation, which is driven by an enhanced glycolytic metabolic program in OSCC cells.

Associations of epidermal growth factor with melanocytes and melanogenesis in the process of skin wound healing

Wound healing is a complex process involving inflammation, cell proliferation, matrix deposition and tissue remodeling. Various cells and cytokines can promote wound healing. Epidermal growth factor (EGF) is considered as a key factor for wound healing. The positive role of EGF in the process of skin wound healing has been confirmed in many animal experiments and clinical practice. However, associations of EGF with melanocytes and melanogenesis are still unclear during the process of wound repair. Recently, studies have found that EGF can inhibit the production of melanin by melanocytes after laser therapy, so as to improve post-inflammatory pigmentation. Key words: Wounds and injuries; Epidermal growth factor; Melanocytes; Pigmentation; Melamogenesis

995P - Role of epidermal growth factor and its soluble receptor in realization of anti-EGFR monoclonal antibodies effect in patients with head and neck cancer (HNC)

995P - Role of epidermal growth factor and its soluble receptor in realization of anti-EGFR monoclonal antibodies effect in patients with head and neck cancer (HNC)

Egf Signaling Directs Neoblast Repopulation by Regulating Asymmetric Cell Division in Planarians

A large population of proliferative stem cells (neoblasts) is required for physiological tissue homeostasis and post-injury regeneration in planarians. Recent studies indicate that survival of a few neoblasts after sublethal irradiation results in the clonalexpansion of the surviving stem cells and the eventual restoration of tissue homeostasis and regenerative capacity. However, the precise mechanisms regulating the population dynamics of neoblasts remain largely unknown. Here, we uncovered a central role for epidermal growth factor (EGF) signaling during invivo neoblast expansion mediated by Smed-egfr-3 (egfr-3) and its putative ligand Smed-neuregulin-7 (nrg-7). Furthermore, the EGF receptor-3 protein localizes asymmetrically on thecytoplasmic membrane of neoblasts, and the ratioof asymmetric to symmetric cell divisions decreases significantly in egfr-3(RNAi) worms. Our results not only provide the first molecular evidence of asymmetric stem cell divisions in planarians, but also demonstrate that EGF signaling likely functionsas an essential regulator of neoblast clonal expansion.

Epidermal growth factor (EGF) triggers the malignancy of hemangioma cells via activation of NF-κB signals.

Hemangioma (HA) is tumor formed by hyper-proliferation of vascular endothelial cells. However, the role and mechanisms of epidermal growth factor (EGF) on the progression of HA are not well illustrated. Our present study revealed that EGF can significantly promote the in vitro proliferation and motility of HA cells, which was confirmed by the up regulation of Bcl-2, proliferating cell nuclear antigen (PCNA), and metalloproteinase-2 (MMP-2) and MMP-9. The pharmacological inhibition of NF-κB, while not ERK1/2 or PI3K/Akt, attenuated EGF induced cell proliferation and expression of MMP-2 and MMP-9. EGF treatment also increased the phosphorylation, nuclear translocation and transcriptional activities of NF-κB in HA cells. These data suggested that NF-κB plays an essential role in EGF induced malignancy of HA cells. Furthermore, EGF treatment also increased the phosphorylation of IκB and IKKα, while not IKKβ or IKKγ. The knockdown of IKKα reversed EGF induced activation of NF-κB. EGF treatment also decreased the phosphorylation of GSK-3β and increased its activities in both HDEC and CRL-2586 EOMA cells. LiCl, a potent GSK-3β inhibitor, can obviously reverse EGF induced up regulation of p65 phosphorylation. Collectively, our study revealed that EGF can trigger the malignancy of HA cells via induction of proliferation and invasion. The activation of NF-κB through IKKα/IκBα and GSK-3β signal is essential for this process. It suggested that EGF/NF-κB signal may represent a novel therapeutic target for the treatment of human HA.