Epithelial derived-matrix metalloproteinase (MMP9) exhibits a novel defensive role of tumor suppressor in colitis associated cancer by activating MMP9-Notch1-ARF-p53 axis
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Lewins Walter1, Adani Pujada1, Noopur Bhatnagar2, Agnieszka B Bialkowska3, Vincent W. Yang3, Hamed Laroui4, Pallavi Garg1
1Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
2Department of Biology, Georgia State University, Atlanta, GA, USA
3Stony Brook University, Department of Medicine, Stony Brook, NY, USA
4Center for Diagnostics and Therapeutics, Department of Chemistry/ Biology, Georgia State University, Atlanta, GA, USA
Pallavi Garg, email: [email protected]
Keywords: MMP9, tumor suppressor, colitis associated cancer, Notch1, γH2AX
Received: June 02, 2016 Accepted: November 11, 2016 Published: November 16, 2016
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.
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