title: Notch1 regulates the effects of matrix metalloproteinase-9 on colitis-associated cancer in mice.
abstract: OBJECTIVE
  Inflammatory bowel disease increases the risks of colon cancer and colitis-associated cancer (CAC). Epithelial cell-derived matrix metalloproteinase (MMP)-9 mediates inflammation during acute colitis and the cleavage and activation of the transcription factor Notch1, which prevents differentiation of progenitor cells into goblet cells. However, MMP-9 also protects against the development of CAC and acts as a tumor suppressor. We investigated the mechanisms by which MMP-9 protects against CAC in mice.
  
  
  METHODS
  C57/B6 wild-type mice were given a single dose of azoxymethane and 2 cycles of dextran sulfate sodium (DSS). Mice were also given the γ-secretase inhibitor difluorophenacetyl-l-alanyl-S-phenylglycine t-butyl ester (DAPT) or dimethyl sulfoxide (control) during each DSS cycle; they were killed on day 56. We analyzed embryonic fibroblasts isolated from wild-type and MMP-9-/- mice and HCT116 cells that were stably transfected with MMP-9.
  
  
  RESULTS
  Wild-type mice were more susceptible to CAC following inhibition of Notch1 by DAPT, shown by increased numbers of tumors and level of dysplasia compared with controls. Inhibition of Notch1 signaling significantly reduced protein levels of active Notch1, p53, p21WAF1/Cip1, Bax-1, active caspase-3, as well as apoptosis, compared with controls. Similar results were observed in transgenic HCT116 cells and embryonic fibroblasts from MMP-9-/- mice on γ-radiation-induced damage of DNA.
  
  
  CONCLUSIONS
  MMP-9 mediates Notch1 signaling via p53 to regulate apoptosis, cell cycle arrest, and inflammation. By these mechanisms, it might prevent CAC.
authors: Division of Digestive Diseases, Department of Pathology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. pallavi7a@gmail.com
authors: Pallavi
authors: P
authors: Garg
authors: Sabrina
authors: S
authors: Jeppsson
authors: Guillaume
authors: G
authors: Dalmasso
authors: Amr M
authors: AM
authors: Ghaleb
authors: Beth B
authors: BB
authors: McConnell
authors: Vincent W
authors: VW
authors: Yang
authors: Andrew T
authors: AT
authors: Gewirtz
authors: Didier
authors: D
authors: Merlin
authors: Shanthi V
authors: SV
authors: Sitaraman
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001397:Azoxymethane; D053148:Caspase 3 / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D003106:Colon / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D016264:Dextran Sulfate; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology / Q000528:radiation effects; D005720:Gamma Rays; D045325:HCT116 Cells; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines; D004151:Dipeptides; D004791:Enzyme Inhibitors; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497762:Notch1 protein, mouse; D012333:RNA, Messenger; D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; D016264:Dextran Sulfate; D053829:Amyloid Precursor Protein Secretases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D001397:Azoxymethane