Résumé
PURPOSE: Molecular treatments targeting epidermal growth factor receptors (EGFRs) are important strategies for advanced colorectal cancer (CRC). However, clinicopathologic implications of EGFRs and EGFR ligand signaling have not been fully evaluated. We evaluated the expression of EGFR ligands and correlation with their receptors, clinicopathologic factors, and patients’ survival with CRC. MATERIALS AND METHODS: The expression of EGFR ligands, including heparin binding epidermal growth factor-like growth factor (HBEGF), transforming growth factor (TGF), betacellulin, and epidermal growth factor (EGF), were evaluated in 331 consecutive CRC samples using mRNA in situ hybridization (ISH). We also evaluated the expression status of EGFR, human epidermal growth factor receptor 2 (HER2), HER3, and HER4 using immunohistochemistry and/or silver ISH. RESULTS: Unlike low incidences of TGF (38.1%), betacellulin (7.9%), and EGF (2.1%), HBEGF expression was noted in 62.2% of CRC samples. However, the expression of each EGFR ligand did not reveal significant correlations with survival. The combined analyses of EGFR ligands and EGFR expression indicated that the ligands–/EGFR+ group showed a significant association with the worst disease-free survival (DFS; p=0.018) and overall survival (OS; p=0.005). It was also an independent, unfavorable prognostic factor for DFS (p=0.026) and OS (p=0.007). Additionally, HER4 nuclear expression, regardless of ligand expression, was an independent, favorable prognostic factor for DFS (p=0.034) and OS (p=0.049), by multivariate analysis. CONCLUSION: Ligand-independent EGFR overexpression was suggested to have a significant prognostic impact; thus, the expression status of EGFR ligands, in addition to EGFR, might be necessary for predicting patients' outcome in CRC.
Sujets)
Humains , Bêtacelluline , Tumeurs colorectales , Survie sans rechute , Facteur de croissance épidermique , Héparine , Immunohistochimie , Hybridation in situ , Incidence , Ligands , Analyse multifactorielle , Pronostic , Récepteurs ErbB , ARN messager , Argent , Facteurs de croissance transformantsRésumé
Type 1 diabetes is an autoimmune disease caused by permanent destruction of insulin-producing pancreatic beta cells and requires lifelong exogenous insulin therapy. Recently, islet transplantation has been developed, and although there have been significant advances, this approach is not widely used clinically due to the poor survival rate of the engrafted islets. We hypothesized that improving survival of engrafted islets through ex vivo genetic engineering could be a novel strategy for successful islet transplantation. We transduced islets with adenoviruses expressing betacellulin, an epidermal growth factor receptor ligand, which promotes beta-cell growth and differentiation, and transplanted these islets under the renal capsule of streptozotocin-induced diabetic mice. Transplantation with betacellulin-transduced islets resulted in prolonged normoglycemia and improved glucose tolerance compared with those of control virus-transduced islets. In addition, increased microvascular density was evident in the implanted islets, concomitant with increased endothelial von Willebrand factor immunoreactivity. Finally, cultured islets transduced with betacellulin displayed increased proliferation, reduced apoptosis and enhanced glucose-stimulated insulin secretion in the presence of cytokines. These experiments suggest that transplantation with betacellulin-transduced islets extends islet survival and preserves functional islet mass, leading to a therapeutic benefit in type 1 diabetes.
Sujets)
Animaux , Humains , Souris , Rats , Apoptose , Bêtacelluline , Prolifération cellulaire , Diabète expérimental/chirurgie , Intolérance au glucose/chirurgie , Cellules à insuline/métabolisme , Protéines et peptides de signalisation intercellulaire/génétique , Transplantation d'ilots de Langerhans , Souris de lignée C57BLRésumé
In the present study, we investigate the expression profile of the epidermal growth factor receptor family, which comprises EGFR/ErbB1, HER2/ErbB2, HER3/ErbB3 and HER4/ErbB4 in oral leukoplakia (LP). The expression of four epidermal growth factor receptor (EGFR) family genes and their ligands were measured in LP tissues from 14 patients and compared with levels in 10 patients with oral lichen planus (OLP) and normal oral mucosa (NOM) from 14 healthy donors by real-time polymerase chain reaction (PCR) and immunohistochemistry. Synchronous mRNA coexpression of ErbB1, ErbB2, ErbB3 and ErbB4 was detected in LP lesions. Out of the receptors, only ErbB4 mRNA and protein was more highly expressed in LP compared with NOM tissues. These were strongly expressed by epithelial keratinocytes in LP lesions, as shown by immunohistochemistry. Regarding the ligands, the mRNA of Neuregulin2 and 4 were more highly expressed in OLP compared with NOM tissues. Therefore, enhanced ErbB4 on the keratinocytes and synchronous modulation of EGFR family genes may contribute to the pathogenesis and carcinogenesis of LP.
Sujets)
Adulte , Sujet âgé , Femelle , Humains , Mâle , Adulte d'âge moyen , Amphiréguline , Bêtacelluline , Protéines de la famille de l'EGF , Facteur de croissance épidermique , Métabolisme , Épiréguline , Analyse de profil d'expression de gènes , Glycoprotéines , Métabolisme , Héparine , Métabolisme , Facteur de croissance de type EGF liant l'héparine , Protéines et peptides de signalisation intercellulaire , Métabolisme , Kératinocytes , Métabolisme , Leucoplasie buccale , Métabolisme , Lichen plan buccal , Métabolisme , Ligands , Muqueuse de la bouche , Métabolisme , Facteurs de croissance nerveuse , Neurégulines , Métabolisme , ARN messager , Métabolisme , Réaction de polymérisation en chaine en temps réel , Récepteurs ErbB , Métabolisme , Récepteur ErbB-2 , Métabolisme , Récepteur ErbB-3 , Métabolisme , Récepteur ErbB-4 , Récepteurs de surface cellulaire , Métabolisme , Facteur de croissance transformant alpha , Métabolisme , Régulation positive , PhysiologieRésumé
The sigma-1 receptor is a molecular chaperone protein highly enriched in the brain. Recent studies linked it to many diseases, such as drug addition, Alzheimer's disease, stroke, depression, and even cancer. Sigma-1 receptor is enriched in lipid rafts, which are membrane microdomains essential in signaling processes. One of those signaling processes is ADAM17- and ADAM10-dependent ectodomain shedding. By using an alkaline phosphatase tagged substrate reporter system, we have shown that ADAM10-dependent BTC shedding was very sensitive to both membrane lipid component change and sigma-1 receptor agonist DHEAS treatment while ADAM17-dependent HB-EGF shedding was not; and overexpression of sigma-1 receptor diminished ADAM17- and ADAM10-dependent shedding. Our results indicate that sigma-1 receptor plays an important role in modifying the function of transmembrane proteases.
Sujets)
Animaux , Humains , Protéines ADAM , Métabolisme , Protéine ADAM10 , Protéine ADAM17 , Amyloid precursor protein secretases , Métabolisme , Bêtacelluline , Cellules COS , Chlorocebus aethiops , Expression des gènes , Cellules HEK293 , Facteur de croissance de type EGF liant l'héparine , Protéines et peptides de signalisation intercellulaire , Métabolisme , Microdomaines membranaires , Métabolisme , Protéines membranaires , Métabolisme , Récepteur sigma , MétabolismeRésumé
Epidermal growth factor receptor (EGFR) cell signaling plays a central role in beta-cell mass/function regulation, and provides a new strategy for the treatment of diabetes, but its mechanisms of action remain poorly understood. In developmental biology, pancreatic islet development is impaired in lacking EGFR of mice. The attenuation of EGFR signaling in the islets leads to markedly reduced beta-cell proliferation. EGFR ligands BTC can increase proliferation and neogenesis. In this article EGFR and their ligands in the pancreas, EGFR cell signaling, and EGFR effects in pancreatic beta-cell mass/function regulation were reviewed.