There is a well−documented association of matrix metalloproteinase−9 (MMP−9) and receptor Notch−1 overexpression in colon cancer. We recently showed that MMP−9 is also upregulated in colitis, where it modulates tissue damage and goblet cell differentiation via proteolytic cleavage of Notch−1. In this study, we investigated whether MMP−9 is critical for colitis−associated colon cancer (CAC). Mice that are wild type (WT) or MMP−9 nullizygous (MMP−9(−/−)) were used for in vivo studies and the human enterocyte cell line Caco2−BBE was used for in vitro studies. CAC was induced in mice using an established carcinogenesis protocol that involves exposure to azoxymethane followed by treatment with dextran sodium sulfate. MMP−9(−/−) mice exhibited increased susceptibility to CAC relative to WT mice. Elevations in tumor multiplicity, size, and mortality were associated with increased proliferation and decreased apoptosis. Tumors formed in MMP−9(−/−) mice exhibited expression of p21(WAF1/Cip1) and increased expression of beta−catenin relative to WT mice. In vitro studies of MMP−9 overexpression showed increased Notch−1 activation with a reciprocal decrease in beta−catenin. Notch and beta−catenin/Wnt signaling have crucial roles in determining differentiation and carcinogenesis in gut epithelia. Despite being a mediator of proinflammatory responses in colitis, MMP−9 plays a protective role and acts as a tumor suppressor in CAC by modulating Notch−1 activation, thereby resulting in activation of p21(WAF1/Cip1) and suppression of beta−catenin.

PMCID: PMC2821688 [Available on 2011/1/15]; PMID: 20068187 [PubMed − indexed for MEDLINE] Source: National Library of Medicine.