Matrix metalloproteinase MMP9 maintains epithelial barrier function and preserves mucosal lining in colitis associated cancer

Abstract

In colitis associated cancer (CAC), chronic inflammation exposes the epithelial mucosal defensive lining to inflammatory mediators such as cytokines and anti-microbial peptides (AMPs) causing the dysbiosis of microbiota population and the dysregulation of immune response. Matrix Metalloproteinases (MMPs) are zinc dependent endopeptidases which mediate inflammation, tissue remodeling, and carcinogenesis. MMP9 is undetectable in healthy tissue, although highly upregulated during inflammation and cancer. We have previously shown that MMP9 plays a protective role in CAC opposite to its conventional role of acute inflammation and cancer mediator. In this study, we investigated the mechanistic role of MMP9 in preserving the epithelial mucosal integrity to suppress the progression of tumor microenvironment in CAC. We used transgenic mice constitutively expressing MMP9 in colonic epithelium (TgM9) as an in vivo model and intestinal cell line CaCo2BBE as an in vitro model. We induced CAC with three cycles of dextran sodium sulfate (DSS). We observed that MMP9 expression in colonic epithelium maintains the microbiota. We also observed that MMP9 mediates pro-inflammatory cytokine levels and AMPs but suppresses IL-22 resulting in lower levels of REG3-g and S100A8 AMPs. We also found that MMP9 maintains an efficient barrier function and the integrity of tight junctions. We also observed increased levels of mucin and intestinal trefoil factor among TgM9 mice in CAC. We also found that MMP9 expressing CaCo2BBE cells had increased expressions of EGFR and nuclear transcription factor- specificity protein 1 (Sp1). These data imply that MMP9 acts as a tumor suppressor in CAC by sustaining the epithelial mucosal integrity due to the activation of EGFR-Sp1 signaling pathway.

Anti-metastatic and anti-proliferative activity of eugenol against triple negative and HER2 positive breast cancer cells

“…Multiple signaling pathways regulate the expression of MMPs [ 35 , 36 ]. Thus, targeting genes in these signaling pathways may suppress or decrease metastasis and consequently reduce cancer mortality.…”

Matrix Metalloproteinase-9 (MMP-9) as a Cancer Biomarker and MMP-9 Biosensors: Recent Advances

“…For instance, MMP-9 has been found to play a role in tumor invasion, metastasis and angiogenesis and to mediate tumor microenvironment [ 45 , 64 , 65 , 66 , 67 , 68 , 69 , 73 , 74 , 75 ]. MMP-9 promotes cancer development and progression in most cases, and it can also play a suppressive role in cancer progression in some specific cases, such as colitis-associated colon cancer [ 76 , 77 , 78 ]. In addition to cancers, MMP-9 is also associated with the pathologies of some other diseases, including autoimmune diseases and cardiovascular diseases, which will not be addressed in this review [ 17 , 79 , 80 , 81 , 82 , 83 ].…”

Knockdown of Matrix Metallopeptidase 9 Inhibits Metastasis of Oral Squamous Cell Carcinoma Cells in a Zebrafish Xenograft Model

“…In particular, decreasing expression of MMP-9 could inhibit the invasive and metastatic ability of some cancers, such as pancreatic adenocarcinoma [10], lung cancer [11], thyroid cancer [12], and ovarian cancer [13]. But MMP-9 could also maintain the epithelial-mucosal integrity by activating the EGFR-Sp1 signaling pathway, thereby playing a suppressor role in colitis-associated cancer [14]. The overexpression of MMP-9 in human OSCC tissues may contribute to cancer metastasis, suggesting that MMP-9 may serve as a prognostic biomarker of OSCC [15,16].…”