目的:结肠上皮细胞(CEC)增殖失调是结直肠癌发生发展的关键特征。我们表明NF-κB诱导激酶(NIK)通过协调CEC再生/分化通过非经典NF-κB信号传导减弱结直肠癌,这是经典NF-κB信号传导独特的。
方法:初步研究评估了隐窝形态/功能,类器官产生,转录组概况,和微生物组。在施用氧化偶氮甲烷和葡聚糖硫酸钠(AOM/DSS)后,全身NIK敲除小鼠(Niki-/-)和条件敲除小鼠开始炎症和炎症诱导的肿瘤发生。
结果:人类转录组数据显示非规范NF-κB信号传导失调。体外研究评估来自成熟,非分裂CECs和结肠干细胞(CSC)表现出增加的积累和发育迟缓,分别。Nk-/-细胞的转录组学分析揭示了与改变的分化再生相关的基因表达特征。当在体内评估时,在给予DSS的情况下,Nk-/-小鼠表现出更严重的结肠炎和以增加的致结肠微生物群为特征的改变的微生物组。在炎症诱导的肿瘤发生模型中,我们观察到在CEC中NIK被敲除的小鼠中肿瘤负荷和炎症增加(NikACEC)。有趣的是,当NIK在骨髓细胞中被有条件地敲除时(NikAMYE),这没有被概括。令人惊讶的是,骨髓细胞中经典途径的条件性敲除(RelAΔMYE)显示肿瘤负荷和炎症减少,并且在CECs中有条件敲除时没有显着变化(RelAΔCEC)。
结论:非经典NF-κB信号调节异常以组织依赖性方式与结直肠癌的发生发展相关,并定义了NIK在调节胃肠道炎症和与结直肠癌相关的再生中的关键作用。
OBJECTIVE: Dysregulated colonic epithelial cell (CEC) proliferation is a critical feature in the development of colorectal cancer. We show that NF-κB-inducing kinase (NIK) attenuates colorectal cancer through coordinating CEC regeneration/differentiation via noncanonical NF-κB signaling that is unique from canonical NF-kB signaling.
METHODS: Initial studies evaluated crypt morphology/functionality, organoid generation, transcriptome profiles, and the microbiome. Inflammation and inflammation-induced tumorigenesis were initiated in whole-body NIK knockout mice (Nik-/-) and conditional-knockout mice following administration of azoxymethane and dextran sulfate sodium.
RESULTS: Human transcriptomic data revealed dysregulated noncanonical NF-kB signaling. In vitro studies evaluating Nik-/- crypts and organoids derived from mature, nondividing CECs, and colonic stem cells exhibited increased accumulation and stunted growth, respectively. Transcriptomic analysis of Nik-/- cells revealed gene expression signatures associated with altered differentiation-regeneration. When assessed in vivo, Nik-/- mice exhibited more severe colitis with dextran sulfate sodium administration and an altered microbiome characterized by increased colitogenic microbiota. In the inflammation-induced tumorigenesis model, we observed both increased tumor burdens and inflammation in mice where NIK is knocked out in CECs (NikΔCEC). Interestingly, this was not recapitulated when NIK was conditionally knocked out in myeloid cells (NikΔMYE). Surprisingly, conditional knockout of the canonical pathway in myeloid cells (RelAΔMYE) revealed decreased tumor burden and inflammation and no significant changes when conditionally knocked out in CECs (RelAΔCEC).
CONCLUSIONS: Dysregulated noncanonical NF-κB signaling is associated with the development of colorectal cancer in a tissue-dependent manner and defines a critical role for NIK in regulating gastrointestinal inflammation and regeneration associated with colorectal cancer.