Epithelial derived-matrix metalloproteinase (MMP9) exhibits a novel defensive role of tumor suppressor in colitis associated cancer by activating MMP9-Notch1-ARF-p53 axis

Autor: Adani Pujada, Vincent W. Yang, Agnieszka B. Bialkowska, Hamed Laroui, Lewins Walter, Noopur Bhatnagar, Pallavi Garg
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
colitis associated cancer
Cyclin E
Apoptosis
MMP9
Inflammatory bowel disease
Mice
0302 clinical medicine
γH2AX
Intestinal Mucosa
Receptor
Notch1
Caspase 3
Dextran Sulfate
Colitis
3. Good health
Tumor Burden
Oncology
Matrix Metalloproteinase 9
030220 oncology & carcinogenesis
Colonic Neoplasms
S Phase Cell Cycle Checkpoints
medicine.symptom
Research Paper
Signal Transduction
Genetically modified mouse
Cyclin-Dependent Kinase Inhibitor p21
DNA damage
tumor suppressor
Colon
Inflammation
Mice
Transgenic
Transfection
03 medical and health sciences
medicine
Animals
Humans
Cyclin-Dependent Kinase Inhibitor p16
Cell Proliferation
Notch1
business.industry
Tumor Suppressor Proteins
Neoplasms
Experimental
Fibroblasts
medicine.disease
HCT116 Cells
body regions
Mice
Inbred C57BL
030104 developmental biology
Immunology
Cancer research
Tumor Suppressor Protein p53
business
DNA Damage
Zdroj: Oncotarget
ISSN: 1949-2553
Popis: 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.
Databáze: OpenAIRE
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