Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Proc Natl Acad Sci U S A. 2012 Aug 28;109(35):14007-12. doi: 10.1073/pnas.1211509109. Epub 2012 Aug 14.
The role of NF-κB activation in tumor initiation has not been thoroughly investigated. We generated Ikkβ(EE)(IEC) transgenic mice expressing constitutively active IκB kinase β (IKKβ) in intestinal epithelial cells (IECs). Despite absence of destructive colonic inflammation, Ikkβ(EE)(IEC) mice developed intestinal tumors after a long latency. However, when crossed to mice with IEC-specific allelic deletion of the adenomatous polyposis coli (Apc) tumor suppressor locus, Ikkβ(EE)(IEC) mice exhibited more β-catenin(+) early lesions and visible small intestinal and colonic tumors relative to Apc(+/ΔIEC) mice, and their survival was severely compromised. IEC of Ikkβ(EE)(IEC) mice expressed high amounts of inducible nitric oxide synthase (iNOS) and elevated DNA damage markers and contained more oxidative DNA lesions. Treatment of Ikkβ(EE)(IEC)/Apc(+/ΔIEC) mice with an iNOS inhibitor decreased DNA damage markers and reduced early β-catenin(+) lesions and tumor load. The results suggest that persistent NF-κB activation in IEC may accelerate loss of heterozygocity by enhancing nitrosative DNA damage.
NF-κB 激活在肿瘤起始中的作用尚未被深入研究。我们生成了在肠上皮细胞（IEC）中表达组成型激活的 IκB 激酶β（IKKβ）的 IKKβ（EE）（IEC）转基因小鼠。尽管没有破坏性的结肠炎症，但 IKKβ（EE）（IEC）小鼠在很长的潜伏期后发展出了肠道肿瘤。然而，当与具有 IEC 特异性等位基因缺失的腺瘤性结肠息肉病（Apc）肿瘤抑制基因座的小鼠杂交时，与 Apc（+/ΔIEC）小鼠相比，IKKβ（EE）（IEC）小鼠表现出更多的β-连环蛋白（+）早期病变和可见的小肠和结肠肿瘤，并且它们的存活率严重受损。IKKβ（EE）（IEC）小鼠的 IEC 表达大量诱导型一氧化氮合酶（iNOS）和升高的 DNA 损伤标志物，并含有更多的氧化 DNA 损伤。用 iNOS 抑制剂治疗 IKKβ（EE）（IEC）/Apc（+/ΔIEC）小鼠可降低 DNA 损伤标志物并减少早期β-连环蛋白（+）病变和肿瘤负荷。结果表明，IEC 中持续的 NF-κB 激活可能通过增强硝化 DNA 损伤加速杂合性丢失。
