title: Heparin-binding epidermal growth factor-like growth factor: a hepatic stellate cell proliferation inducer via ErbB receptors.
abstract: OBJECTIVE
  Heparin-binding epidermal growth factor-like growth factor (HB-EGF) has a proliferative effect on several types of cells. However, the role of HB-EGF on hepatic stellate cells (HSCs) is not clear. The present study is to investigate the regulatory effects of HB-EGF on HSC proliferation and apoptosis.
  
  
  METHODS
  Activated primary rat HSCs and two HSC cell lines (human LX2 and rat T6) were used in this study. Four inhibitors (CRM197 to HB-EGF, AG1478 to epidermal growth factor receptor [EGFR], PD98059 to mitogen-activated kinase, and LY294002 to phosphatidylinositol 3-kinase) were employed to verify the pathway of HB-EGF on cell proliferation and apoptosis.
  
  
  RESULTS
  HB-EGF expression was significantly increased in activated HSCs. HB-EGF increased the expressions of phospho-EGFR and ErbB4 receptors, the phosphorylation of extracellular signal-regulated kinase (ERK) and Akt. Consequently, HB-EGF stimulated HSC proliferation and suppressed HSC apoptosis. Each individual inhibitor specifically inhibited the correlated receptor or enzyme and inhibited HSC proliferation and induced its apoptosis.
  
  
  CONCLUSIONS
  HB-EGF promotes HSC proliferation via activation of the EGFR and ErbB4 receptors and, subsequently, via activation of ERK and Akt. Any blockage in the chain obstructs the flow from HB-EGF to HSC proliferation. Therefore, HB-EGF is a potential therapeutic target in liver fibrosis.
authors.affiliation: Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology, Hebei Institute of Gastroenterology, Shijiazhuang, Hebei Province, China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Jiang
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Junji
authors.initials: J
authors.lastname: Ma
authors.forename: Huiqing
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D066257:Heparin-binding EGF-like Growth Factor; D055166:Hepatic Stellate Cells / Q000166:cytology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008297:Male; D058990:Molecular Targeted Therapy; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D066247:Receptor, ErbB-4; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: C587883:HBEGF protein, human; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; C587689:ERBB4 protein, human; C483803:Egfr protein, rat; D066246:ErbB Receptors; C587691:Erbb4 protein, rat; D066247:Receptor, ErbB-4; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: apoptosis; epidermal growth factor receptor; heparin-binding epidermal growth factor-like growth factor; hepatic stellate cells; proliferation