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PALLAVI GARG Ph.D.

PALLAVI GARG Ph.D. Overexpression of MMP9 in colonic epithelium mediates protection in colitis associated cancer. Disclosures. Nothing to Disclose. Matrix Metalloproteinases (MMPs).

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PALLAVI GARG Ph.D.

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  1. PALLAVI GARG Ph.D. Overexpression of MMP9 in colonic epithelium mediates protection in colitis associated cancer

  2. Disclosures Nothing to Disclose

  3. Matrix Metalloproteinases (MMPs) Are a family of zinc-dependent proteolytic enzymes with the ability to degrade extracellular matrix substrates such as collagen, gelatin and proteoglycans

  4. Colitis Associated Cancer (CAC) & Colorectal Cancer • CAC is an important complication of Ulcerative Colitis or colonic Crohn’s Disease that results in significant morbidity and mortality • It causes 1/6 of all deaths in patients with ulcerative colitis • Colon cancer develops in flat dysplastic tissue among IBD individuals • CAC is often multiple, anaplastic, broadly infiltrating, rapidly growing and occurs at a younger age • The pathogenesis of CAC is not known

  5. MMP9 is not expressed in normal tissues and is one of the predominant MMPs that is up-regulated in several animal models of colitis and human IBD • MMP9 mRNA and protein levels are increased in the inflamed colonic mucosa of patients with IBD • MMP9 activity correlates with active inflammation • MMP9 activates Notch1 signaling in colonic epithelium MMP9 and its role in acute colitis Castaneda et al, 2005, Gastroenterology Garg et al, 2007, Gastroenterology

  6. Role of MMP9 in CAC • MMP9-/- mice show increased susceptibility to CAC • CAC in MMP9-/- mice is associated with decreased apoptosis compared to WT mice • CAC in MMP9-/- mice showed decreased levels of p21WAF1/Cip1 and p53 • MMP9 mediates its tumor suppressive role via activation of Notch1 signaling Garg et al, 2010, Cancer Research Garg et al, 2011, Gastroenterology

  7. Aim Which MMP9 protects from CAC ?

  8. In vivo model C57/B6 WT Tg-villin-MMP9 DSS (3 cycles) Water DSS (3 cycles) Water DSS= Dextran Sodium Sulfate (3% in drinking water)

  9. In vivo protocol 85 53 DSS Cycle(3rd ) starts sacrifice Days 49 0 28 14 35 7 Recovery (3rd) starts DSS Cycle (1st) starts DSS Cycle(2nd ) starts Recovery (1st) starts Recovery (2nd) starts

  10. Overexpression of epithelial MMP9 exhibited resistance to CAC * * * * Body weight gain in percentage 1 2 3 Tg-villin-MMP9 WT Sacrifice DSS cycle 2 DSS cycle 3 DSS cycle 1 Recovery cycle 2 Recovery cycle 3 Recovery cycle 1

  11. Overexpression of epithelial MMP9 exhibited less tumor incidence in CAC B A Number of polyps Number of dysplastic lesions * Tg-villin-MMP9 CAC WT CAC Tg-villin-MMP9 CAC WT CAC

  12. Overexpression of epithelial MMP9 exhibited resistance to CAC X20 X10 WT CAC Tg-villin-MMP9 CAC

  13. Overexpression of epithelial MMP9 showed increased levels of Notch1and p53 in CAC Tg-villin-MMP9, CAC A WT, CAC MMP9, 104 kD β-tubulin 1 2 3 4 5 6 Tg-villin-MMP9, CAC WT, CAC B NICD, 80 kD β-tubulin 1 2 3 4 5 6 Tg-villin-MMP9, CAC WT, CAC C p53, 53 kD GAPDH 1 2 3 4 5 6

  14. Overexpression of epithelial MMP9 showed increased levels of p21WAF1/Cip1and Bax1 in CAC Tg-villin-MMP9, CAC WT, CAC A p21WAF1/Cip1, 21kD GAPDH 1 2 3 4 5 6 Tg-villin-MMP9, CAC B WT, CAC Bax-1, 37 kD GAPDH 1 2 3 4 5 6

  15. Overexpression of MMP9 in MMP9-/- MEFs showed increased levels of Notch1 and p53 WT MEFs MMP9-/- MEFs MMP9-/-MEFs + MMP9 A MMP-9, 104 kD B NICD, 80 kD GAPDH 1 2 3 4 5 6 WT MEFs MMP9-/- MEFs MMP9-/-MEFs + MMP9 C p53, 53 kD GAPDH 1 2 3 4 5 6

  16. Summary • Epithelial-derived MMP9 plays a tumor suppressive role in CAC • Overexpression of MMP9 in colonic epithelium is associated with altered levels of p53, Notch1, Bax1 and p21WAF1/Cip1 • Overexpression of MMP9 in MMP9-/-exhibited increased levels of NICD and p53

  17. Molecular mechanism of p53 regulation by MMP9 via Notch1 Inflammation nucleus + + + ARF + + Notch-1 Mdm2 MMP-9 ARF Mdm2 - cytosol p53 Mdm2

  18. Conclusions • Despite being a mediator of acute inflammation, epithelial derived- MMP9 acts as a tumor suppressor in CAC • MMP9 mediated p53 activation via Notch1 signaling is necessary and sufficient for its tumor suppressive effect in CAC

  19. Acknowledgement Didier Merlin Lewins Walter Crohn’s & Colitis Foundation of AmericaCareer Development Award, (#3057)

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