Notch1 regulates the effects of matrix metalloproteinase-9 on colitis-associated cancer in mice.
Notch1 regulates the effects of matrix metalloproteinase-9 on colitis-associated cancer in mice.
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DOI：
10.1053/j.gastro.2011.06.056
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发表时间：
2011-10
期刊：
影响因子：
29.4
通讯作者：
Sitaraman SV
中科院分区：
文献类型：
--
作者：
Garg P;Jeppsson S;Dalmasso G;Ghaleb AM;McConnell BB;Yang VW;Gewirtz AT;Merlin D;Sitaraman SV
炎症性肠病会增加结肠癌和结肠炎相关癌症（CAC）的风险。上皮细胞来源的基质金属蛋白酶（MMP）9介导急性结肠炎期间的炎症以及转录因子Notch 1的裂解和活化，其阻止祖细胞分化成杯状细胞。然而，MMP 9也可以防止CAC的发展，并作为肿瘤抑制因子。我们研究了MMP 9在小鼠中对抗CAC的机制。给予C57/B6野生型小鼠单剂量的氧化偶氮甲烷和2个周期的葡聚糖硫酸钠（DSS）。在每个DSS周期中，还给予小鼠γ-分泌酶抑制剂DAPT或DMSO（对照）;在第56天处死。我们分析了从野生型和MMP 9 −/−小鼠以及稳定转染MMP 9的HCT 116细胞中分离的胚胎成纤维细胞。与对照组相比，野生型小鼠在通过DAPT抑制Notch 1后对CAC更敏感，表现为肿瘤数量和发育异常水平增加。与对照组相比，抑制Notch 1信号转导显著降低了活性Notch 1、p53、p21 WAF 1/Cip 1、Bax-1、活性caspase-3的蛋白水平以及细胞凋亡。在转基因HCT 116细胞和MMP 9 −/−小鼠的胚胎成纤维细胞中，在γ辐射诱导的DNA损伤后观察到类似的结果。MMP 9通过p53介导Notch 1信号传导来调节细胞凋亡、细胞周期停滞和炎症。通过这些机制，它可能会阻止CAC。
Inflammatory bowel disease increases the risks for colon cancer and colitis-associated cancer (CAC). Epithelial cell-derived matrix metalloproteinase (MMP)9 mediates inflammation during acute colitis and the cleavage and activation of the transcription factor Notch1, which prevents differentiation of progenitor cells into goblet cells. However, MMP9, also protects against the development of CAC and acts as a tumor suppressor. We investigated the mechanisms by which MMP9 protects against CAC in mice. C57/B6 wild-type mice were given a single dose of azoxymethane and 2 cycles of dextran sulfate sodium (DSS). Mice were also given the γ-secretase inhibitor DAPT or DMSO (control) during each DSS cycle; they were sacrificed on day 56. We analyzed embryonic fibroblasts isolated from wild-type and MMP9−/− mice and HCT116 cells that were stably transfected with MMP9. Wild-type mice were more susceptible to CAC following inhibition of Notch1 by DAPT, demonstrated by increased numbers of tumors and level of dysplasia, compared with controls. Inhibition of Notch1 signaling significantly reduced protein levels of active Notch1, p53, p21WAF1/Cip1, Bax-1, active caspase-3, as well as apoptosis, compared with controls. Similar results were observed in transgenic HCT116 cells and embryonic fibroblasts from MMP9−/− mice, upon γ-radiation–induced damage of DNA. MMP9 mediates Notch1 signaling via p53 to regulate apoptosis, cell-cycle arrest, and inflammation. By these mechanisms, it might prevent CAC.
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影响因子：
11.2
作者：
Garg P;Sarma D;Jeppsson S;Patel NR;Gewirtz AT;Merlin D;Sitaraman SV
通讯作者：
Sitaraman SV
影响因子：
15.9
作者：
Balint, K;Xiao, M;Liu, ZJ
通讯作者：
Liu, ZJ
影响因子：
29.4
作者：
Castaneda, FE;Walia, B;Sitaraman, SV
通讯作者：
Sitaraman, SV
影响因子：
4.7
作者：
Cooper, HS;Murthy, S;Flanigan, A
通讯作者：
Flanigan, A
影响因子：
50.3
作者：
Grivennikov S;Karin E;Terzic J;Mucida D;Yu GY;Vallabhapurapu S;Scheller J;Rose-John S;Cheroutre H;Eckmann L;Karin M
通讯作者：
Karin M