Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Doctor Aiguader 88, 08003 Barcelona, Spain.
DSB Repair Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
Br J Cancer. 2018 Mar 20;118(6):839-846. doi: 10.1038/bjc.2017.459. Epub 2018 Feb 13.
Colorectal cancer is a common cause of death in developed countries. Progression from adenoma to invasive carcinoma requires accumulation of mutations starting with the Adenomatous Polyposis Coli (Apc) gene. NF-κB signalling is a key element in cancer, mainly related to the activity of IKKβ. IKKα kinase also participates in this process by mechanisms that are primarily unknown.
We generated a compound mouse model with mutation in Apc and lacking intestinal epithelial IKKα, produced intestinal organoids and tumour spheroids with different genetic backgrounds, and performed immunohistochemistry and RNA-seq analysis.
Deficiency of IKKα prevents adenoma formation, with adenomas lacking IKKα showing reduced proliferation. In contrast, IKKα status did not affect normal intestinal function. The same divergent phenotype was found in the organoid-spheroid model. We also found that epithelial IKKα controls stemness, proliferation and apoptosis-related expression.
IKKα is a potential therapeutic target for Apc mutant colorectal cancer patients.
结直肠癌是发达国家常见的死亡原因。从腺瘤进展为浸润性癌需要从腺瘤性息肉病 coli(Apc)基因开始积累突变。NF-κB 信号转导是癌症的一个关键因素，主要与 IKKβ的活性有关。IKKα激酶也通过主要未知的机制参与这一过程。
我们生成了一种具有 Apc 突变和缺乏肠上皮细胞 IKKα的复合小鼠模型，生成了具有不同遗传背景的肠类器官和肿瘤球体，并进行了免疫组织化学和 RNA-seq 分析。
IKKα的缺失可预防腺瘤的形成，缺乏 IKKα的腺瘤显示增殖减少。相比之下，IKKα状态并不影响正常的肠道功能。在类器官球体模型中也发现了同样的发散表型。我们还发现上皮 IKKα控制着干细胞特性、增殖和凋亡相关表达。
IKKα是 Apc 突变结直肠癌患者的潜在治疗靶点。
