Udden S M Nashir, Peng Lan, Gan Jia-Liang, Shelton John M, Malter James S, Hooper Lora V, Zaki Md Hasan
Department of Pathology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Molecular Pathology Core, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Cell Rep. 2017 Jun 27;19(13):2756-2770. doi: 10.1016/j.celrep.2017.05.084.
Although NOD2 is the major inflammatory bowel disease susceptibility gene, its role in colorectal tumorigenesis is poorly defined. Here, we show that Nod2-deficient mice are highly susceptible to experimental colorectal tumorigenesis independent of gut microbial dysbiosis. Interestingly, the expression of inflammatory genes and the activation of inflammatory pathways, including NF-κB, ERK, and STAT3 are significantly higher in Nod2 mouse colons during colitis and colorectal tumorigenesis, but not at homeostasis. Consistent with higher inflammation, there is greater proliferation of epithelial cells in hyperplastic regions of Nod2 colons. In vitro studies demonstrate that, while NOD2 activates the NF-κB and MAPK pathways in response to MDP, it inhibits TLR-mediated activation of NF-κB and MAPK. Notably, NOD2-mediated downregulation of NF-κB and MAPK is associated with the induction of IRF4. Taken together, NOD2 plays a critical role in the suppression of inflammation and tumorigenesis in the colon via downregulation of the TLR signaling pathways.
尽管NOD2是主要的炎症性肠病易感基因，但其在结直肠癌发生中的作用仍不清楚。在此，我们表明Nod2基因缺陷小鼠对实验性结直肠癌发生高度易感，且与肠道微生物生态失调无关。有趣的是，在结肠炎和结直肠癌发生过程中，Nod2基因缺陷小鼠结肠中炎症基因的表达以及包括NF-κB、ERK和STAT3在内的炎症信号通路的激活显著高于稳态时，但在稳态时无此现象。与更高的炎症水平一致，Nod2基因缺陷小鼠结肠增生区域的上皮细胞增殖更为明显。体外研究表明，虽然NOD2在响应MDP时激活NF-κB和MAPK信号通路，但它抑制TLR介导的NF-κB和MAPK激活。值得注意的是，NOD2介导的NF-κB和MAPK下调与IRF4的诱导有关。综上所述，NOD2通过下调TLR信号通路在抑制结肠炎症和肿瘤发生中起关键作用。
