title: Matrix metalloproteinases-9 deficiency impairs liver regeneration through epidermal growth factor receptor signaling in partial hepatectomy mice.
abstract: BACKGROUND
  Liver regeneration is a complex process regulated by many complex mechanisms involving cytokines, growth factors, metabolic networks, and so forth. Previous investigations have demonstrated that matrix metalloproteinase-9 (MMP-9) is an essential factor in liver regeneration. The present study aimed to explore the role of MMP-9 in epidermal growth factor receptor (EGFR) signaling and related proliferation signaling factors in a mouse partial hepatectomy (PH) model.
  
  
  METHODS
  MMP-9 knockout (KO) and wild-type mice were used to establish the PH model. Liver regeneration was analyzed based on proliferation cell nuclear antigen immunohistochemistry and liver weight to body weight ratio. Also, EGFR ligands, EGFR, and downstream factors were measured by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot.
  
  
  RESULTS
  MMP-9 KO mice showed a delayed hepatic regenerative response after PH. EGFR ligands, including heparin-binding epidermal growth factor and amphiregulin, were expressed at significantly lower levels between days 1 and 3 posthepatectomy in MMP-9 KO mice. MMP-9 KO mice also inhibited and delayed EGFR activation after PH. After PH, the expression of STAT3, NF-κB, and cyclinD1, all downstream of EGFR, was similar to EGFR activation.
  
  
  CONCLUSIONS
  Our data provide new evidence supporting a critical role of MMP-9 in liver regeneration after PH through activation of EGFR signaling.
authors.affiliation: Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health, Nanjing, Jiangsu Province, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health, Nanjing, Jiangsu Province, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health, Nanjing, Jiangsu Province, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Rao
authors.affiliation: Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health, Nanjing, Jiangsu Province, China.
authors.forename: Zhenchao
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health, Nanjing, Jiangsu Province, China.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health, Nanjing, Jiangsu Province, China. Electronic address: lvling@njmu.edu.cn.
authors.forename: Ling
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health, Nanjing, Jiangsu Province, China. Electronic address: liguoqiang@njmu.edu.cn.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Li
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism*; D006498:Hepatectomy; D008099:Liver / Q000201:enzymology* / Q000502:physiology / Q000601:surgery; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency*; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D015415:Biomarkers; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: Amphiregulin; EGFR; HB-EGF; Liver regeneration; MMP-9