title: Epithelial derived-matrix metalloproteinase (MMP9) exhibits a novel defensive role of tumor suppressor in colitis associated cancer by activating MMP9-Notch1-ARF-p53 axis.
abstract: Colitis associated cancer (CAC) is chronic inflammation driven colon cancer, prevalent among individuals with Inflammatory Bowel Disease. Matrix-metalloproteinase (MMP9) is one of the essential regulators of extra cellular matrix components. We have shown that MMP9 is protective in CAC contrary to its inflammatory role in acute-colitis. Aim of our study is to identify the mechanism of the protective role of epithelial derived-MMP9 in CAC. We used homozygous transgenic mice constitutively-expressing MMP9 in colonic-epithelium (TgM9) and wild-type (WT) littermates for in vivo experiments. Stably-transfected HCT116 with/without MMP9, and mouse embryonic-fibroblasts (WT and MMP9-/-, MEFs) were used for in vitro experiments. TgM9 mice exhibited less tumor burden, increased apoptosis, and increased expressions of active-Notch1, p53, p21WAF1/Cip1, caspase-3 and cyclin E in CAC compared to WTs. These results were supported by MEFs data. HCT116-cells overexpressing MMP9 indicated decreased cell proliferation, S-phase cell-cycle arrest and less DNA damage compared to vector. MMP9-/- mice showed attenuation of MMP9 was directly associated with p19ARF. Our study identifies the tumor suppressor role of epithelial derived-MMP9 in CAC via novel mechanistic pathway "MMP9-Notch1-ARF-p53 axis" regulating apoptosis, cell-cycle arrest and DNA damage implying, that MMP9 expression might be a natural/biological way to suppress colonic ulceration due to chronic inflammation.
authors.affiliation: Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
authors.forename: Lewins
authors.initials: L
authors.lastname: Walter
authors.affiliation: Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
authors.forename: Adani
authors.initials: A
authors.lastname: Pujada
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA, USA.
authors.forename: Noopur
authors.initials: N
authors.lastname: Bhatnagar
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Agnieszka B
authors.initials: AB
authors.lastname: Bialkowska
authors.affiliation: Department of Medicine, Stony Brook University, Stony Brook, NY, USA.
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Yang
authors.affiliation: Department of Chemistry/Biology, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA.
authors.forename: Hamed
authors.initials: H
authors.lastname: Laroui
authors.affiliation: Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Garg
mesh_terms: D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000150:complications / Q000473:pathology*; D003106:Colon / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000209:etiology / Q000473:pathology*; D019927:Cyclin E / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004249:DNA Damage; D016264:Dextran Sulfate / Q000633:toxicity; D005347:Fibroblasts; D045325:HCT116 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000209:etiology / Q000473:pathology; D051881:Receptor, Notch1 / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints; D015398:Signal Transduction; D014162:Transfection; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C417743:Cdkn2a protein, mouse; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D016264:Dextran Sulfate; D053148:Caspase 3; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: MMP9; Notch1; colitis associated cancer; tumor suppressor; γH2AX