Tattoli Ivan, Killackey Samuel A, Foerster Elisabeth G, Molinaro Raphael, Maisonneuve Charles, Rahman Muhammed A, Winer Shawn, Winer Daniel A, Streutker Catherine J, Philpott Dana J, Girardin Stephen E
Department of Laboratory Medicine and Pathobiology, University of Toronto, M5S 1A8 Toronto, Canada; Department of Immunology, University of Toronto, M5S 1A8 Toronto, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, M5S 1A8 Toronto, Canada.
Cell Rep. 2016 Mar 22;14(11):2576-86. doi: 10.1016/j.celrep.2016.02.065. Epub 2016 Mar 10.
The mitochondrial Nod-like receptor protein NLRX1 protects against colorectal tumorigenesis through mechanisms that remain unclear. Using mice with an intestinal epithelial cells (IEC)-specific deletion of Nlrx1, we find that NLRX1 provides an IEC-intrinsic protection against colitis-associated carcinogenesis in the colon. These Nlrx1 mutant mice have increased expression of Tnf, Egf, and Tgfb1, three factors essential for wound healing, as well as increased epithelial proliferation during the epithelial regeneration phase following injury triggered by dextran sodium sulfate. In primary intestinal organoids lacking Nlrx1, stimulation with TNF resulted in exacerbated proliferation and expression of the intestinal stem cell markers Olfm4 and Myb. This hyper-proliferation response was associated with increased activation of Akt and NF-κB pathways in response to TNF stimulation. Together, these results identify NLRX1 as a suppressor of colonic tumorigenesis that acts by controlling epithelial proliferation in the intestine during the regeneration phase following mucosal injury.
线粒体Nod样受体蛋白NLRX1通过尚不清楚的机制预防结直肠癌发生。利用肠道上皮细胞（IEC）特异性缺失Nlrx1的小鼠，我们发现NLRX1为结肠中与结肠炎相关的致癌作用提供了IEC内在保护。这些Nlrx1突变小鼠中，伤口愈合所必需的三个因子Tnf、Egf和Tgfb1的表达增加，并且在葡聚糖硫酸钠引发的损伤后的上皮再生阶段上皮增殖增加。在缺乏Nlrx1的原代肠道类器官中，用TNF刺激会导致肠道干细胞标志物Olfm4和Myb的增殖和表达加剧。这种过度增殖反应与TNF刺激后Akt和NF-κB通路的激活增加有关。总之，这些结果表明NLRX1是结肠肿瘤发生的抑制因子，其通过在粘膜损伤后的再生阶段控制肠道上皮增殖发挥作用。
