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.

结肠炎相关癌症 (CAC) 是结肠癌的一种亚型，由慢性炎症驱动，常见于慢性溃疡性结肠炎患者。CAC 的发展与炎症-发育异常-癌通路有关，该通路与散发性结肠癌 (CRC) 的腺瘤-癌通路显着不同。基质金属蛋白酶 9 (MMP9) 是一种锌依赖性内肽酶，可对抗炎症期间胃肠道中表达的细胞外基质 (ECM) 蛋白。我们之前已经表明 MMP9 通过“MMP9-Notch1-ARF-p53 轴”途径在 CAC 中发挥肿瘤抑制作用。本研究的目的是确定 MMP9 在维持 CAC 基因组稳定性中的作用。在结肠上皮细胞 (TgM9) 中具有组成型表达 MMP9 的纯合转基因小鼠及其野生型同窝仔 (WT) 和稳定转染的 HCT116 细胞（含/不含 MMP9）分别用于体内和体外实验。作为“概念证明”模型，加载有 MMP9 siRNA 的纳米颗粒 (NP) 用于检查结肠上皮中 MMP9 沉默的影响。在 CAC 中，与 WT 相比，TgM9 小鼠的结肠上皮表现出较低量的活性氧 (ROS)、较少的 DNA 损伤和增加的错配修复基因表达。我们的研究表明，MMP9 表达与 ROS 水平降低、DNA 损伤减少和错配修复途径上调相关。这表明 MMP9 表达是一种通过限制结肠中 ROS 积累和 DNA 损伤来抑制 CAC 的自然生物学方式。