title: Suppression of amphiregulin/epidermal growth factor receptor signals contributes to the protective effects of quercetin in cirrhotic rats.
abstract: The hepatic wound-healing response to chronic noxious stimuli may lead to liver fibrosis, a key feature of the preneoplastic cirrhotic liver. Fibrogenic cells activate in response to a variety of cytokines, growth factors, and inflammatory mediators. The involvement of members of the epidermal growth factor family in this process has been suggested. Amphiregulin is an epidermal growth factor receptor (EGFR) ligand specifically induced upon liver injury. We investigated the effects of quercetin on the amphiregulin/EGFR signal and on the activation of downstream pathways leading to cell growth. Rats were divided into 4 groups (8 rats/group): rats subjected to common bile duct ligation (CBDL), Sham (rats subjected to simulated CBDL), quercetin-treated sham, and quercetin-treated CBDL (CBDL-Q). Quercetin (50 mg/kg i.p. injection) was administered daily for 2 wk starting on d 14 after surgery. Overexpression of amphiregulin, EGFR, TNFα, IL-6, TGFβ, platelet-derived growth factor (PDGF), extracellular regulated kinase, protein kinase B (Akt), cycloxygenase (COX)-2, and glioma-associated oncogenes (GLI)-1 and-2 were observed in liver of CBDL rats after 4 wk of bile duct ligation. CBDL-Q rats had a significantly diminished expression of amphiregulin and EGFR compared with untreated CBDL rats. Furthermore, mRNA levels of TNFα, IL-6, TGFβ, and PDGF and the protein content of COX-2, GLI-1, and GLI-2 were significantly lower in CBDL-Q rats than in untreated CBDL rats. The findings indicate that quercetin ameliorated activation of survival pathways and downregulated the expression of genes related to inflammation and precancerous conditions. Suppression of amphiregulin/EGFR signals may contribute to this effect.
authors.affiliation: Institute of Biomedicine, University of León, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, 24071 León, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Cuevas
authors.forename: Juliana
authors.initials: J
authors.lastname: Tieppo
authors.forename: Norma Possa
authors.initials: NP
authors.lastname: Marroni
authors.forename: María J
authors.initials: MJ
authors.lastname: Tuñón
authors.forename: Javier
authors.initials: J
authors.lastname: González-Gallego
mesh_terms: D066258:Amphiregulin; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006133:Growth Substances / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D011794:Quercetin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D000071676:Zinc Finger Protein GLI1
chemical_list: D066258:Amphiregulin; C587849:Areg protein, mouse; C587850:Areg protein, rat; D016207:Cytokines; D066255:EGF Family of Proteins; C498520:Gli1 protein, mouse; D006023:Glycoproteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D000071676:Zinc Finger Protein GLI1; D011794:Quercetin; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D066246:ErbB Receptors