Abstract
Colitis-associated cancer (CAC) is a subtype of colon cancer that is driven by chronic inflammation and is prevalent in chronic ulcerative colitis patients. The development of CAC is associated with the inflammation-dysplasia-carcinoma pathway which is significantly different than adenoma-carcinoma pathway of sporadic colon cancer (CRC). Matrix Metalloproteinase 9 (MMP9) is a zinc-dependent endopeptidase against extracellular matrix (ECM) proteins expressed in the gastrointestinal tract during inflammation. We have previously shown that MMP9 plays a tumor suppressor role in CAC via “MMP9-Notch1-ARF-p53 axis” pathway. The aim of this study is to determine the role of MMP9 in maintaining genomic stability in CAC. Homozygous transgenic mice with constitutive-expression of MMP9 in the colonic epithelium (TgM9) with their wild-type littermates (WT) and stably transfected HCT116 cells with/without MMP9 were used for in vivo and in vitro experiments, respectively. As ‘proof of concept’ model, nanoparticles (NPs) loaded with MMP9 siRNA were used to examine the effect of MMP9 silencing in the colonic epithelium. In CAC, colonic epithelium of TgM9 mice exhibited lower amounts of reactive oxygen species (ROS), less DNA damage, and increased expression of mismatch repair genes compared to WTs. Our study showed that MMP9 expression correlates with the reduced ROS levels, decreased DNA damage, and upregulated mismatch repair pathway. This suggests that MMP9 expression is a natural biological way to suppress CAC by limiting ROS accumulation and DNA damage in the colon. Therefore, MMP9 inhibition could be deleterious for CAC patient.
Highlights
Introduction Inflammatory BowelDisease (IBD), which includes bothCrohn’s Disease (CD) and ulcerative colitis (UC), is chronic inflammatory condition affecting the gastrointestinal (GI) tract[1]
We evaluated the use of Matrix Metalloproteinase 9 (MMP9) neutralizing antibodies for clinical trials with UC patients, with the “proof of concept” in vivo model by silencing MMP9 expression by using MMP9 siRNA loaded nanoparticles (NPs)
TgM9 mice exhibited reduced reactive oxygen species (ROS) levels and DNA damage in CAC We have previously shown that MMP9 has a protective role in CAC
Summary
Crohn’s Disease (CD) and ulcerative colitis (UC), is chronic inflammatory condition affecting the gastrointestinal (GI) tract[1]. CD affects any site in the GI tract from mouth to anus, Individuals with chronically active UC have up to a 50%. (depending on population cohort) risk of developing colitis-associated cancer (CAC), which is driven primarily by distal colon and rectal tumors[4]. Unregulated inflammation can be chronic resulting in malignant cell transformation and cancer[5]. Sporadic colon cancer (CRC) and CAC are both colon cancers. Several features make CAC distinct from CRC6,7. CAC and CRC have different molecular events including initiation, promotion, and progression of Official journal of the Cell Death Differentiation Association
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