Matrix metalloproteinase-9 functions as a tumor suppressor in colitis-associated cancer.
Matrix metalloproteinase-9 functions as a tumor suppressor in colitis-associated cancer.
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DOI：
10.1158/0008-5472.can-09-3166
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发表时间：
2010-01-15
期刊：
影响因子：
11.2
通讯作者：
Sitaraman SV
中科院分区：
文献类型：
--
作者：
Garg P;Sarma D;Jeppsson S;Patel NR;Gewirtz AT;Merlin D;Sitaraman SV
我们已经证明，上皮来源的MMP-9在炎症性肠道疾病期间上调，介导结肠炎期间的组织损伤，并通过结肠中Notch-1的蛋白酶解来调节杯状细胞分化。MMP-9和Notch-1与结肠癌的关联已被充分记录。在这项研究中，我们试图解决的作用和机制，MMP-9介导的结肠炎相关的结肠癌（CAC）。野生型（WT）和MMP-9敲除（MMP-9-/-）小鼠用于体内研究，肠上皮细胞系Caco 2-BBE用于体外研究。采用氧化偶氮甲烷和葡聚糖硫酸钠诱导CAC。MMP-9-/-小鼠表现出对CAC的易感性增加，如肿瘤多样性、大小和死亡率增加所证明的。与WT小鼠中的CAC相比，MMP-9-/-中的CAC与增殖增加和凋亡减少相关。在CAC中，与WT小鼠相比，MMP-9-/-小鼠表现出p21 WAF 1/Cip 1表达，但β-连环蛋白表达增加。MMP-9过表达的体外研究显示Notch-1激活增加，β-连环蛋白相互减少。Notch和β-catenin/Wnt信号是决定肠上皮分化和癌变的重要分子通路。尽管MMP-9是促炎反应的介质，但其在CAC中起保护作用，并通过调节Notch活化而作为肿瘤抑制剂，从而导致p21 WAF 1/Cip 1活化，导致β-连环蛋白的抑制。
We have demonstrated that epithelial derived MMP-9 is upregulated during inflammatory bowel disease, mediates tissue damage during colitis and regulates goblet cell differentiation through proteoltic cleavage of Notch-1 in colon. Association of MMP-9 and Notch-1 with colon cancer has been well documented. In this study, we sought to address the role and mechanism by which MMP-9 mediates the colitis-associated colon cancer (CAC). Wild type (WT) and MMP-9 knock-out (MMP-9-/-) mice were used for in vivo studies and enterocyte cell line, Caco2-BBE, were used for in vitro studies. Azoxymethane and dextran sodium sulfate were used to induce CAC. MMP-9-/- mice showed increased susceptibility to CAC as evidenced by increased tumor multiplicity, size and mortality. CAC in MMP-9-/- is associated with increased proliferation and decreased apoptosis compared to CAC in WT mice. MMP-9-/- mice exhibited p21WAF1/Cip1 expression, but increased β-catenin expression compared to WT mice in CAC. In vitro studies of MMP-9 overexpression showed increased Notch-1 activation and reciprocal decrease in β-catenin. Notch and β-catenin/Wnt signaling are well documented as crucial molecular pathways deciding the gut epithelium differentiation and carcinogenesis. Despite being a mediator of pro-inflammatory response, MMP-9 plays a protective role and acts as a tumor suppressor in CAC by modulating Notch activation resulting in the activation of p21WAF1/Cip1 leading to suppression of β-catenin.