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IKK? is required in the intestinal epithelial cells for tumour stemness.

ABSTRACT: BACKGROUND: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-?B signalling is a key element in cancer, mainly related to the activity of IKK?. IKK? kinase also participates in this process by mechanisms that are primarily unknown. METHODS:We generated a compound mouse model with mutation in Apc and lacking intestinal epithelial IKK?, produced intestinal organoids and tumour spheroids with different genetic backgrounds, and performed immunohistochemistry and RNA-seq analysis. RESULTS:Deficiency of IKK? prevents adenoma formation, with adenomas lacking IKK? showing reduced proliferation. In contrast, IKK? status did not affect normal intestinal function. The same divergent phenotype was found in the organoid-spheroid model. We also found that epithelial IKK? controls stemness, proliferation and apoptosis-related expression. CONCLUSIONS:IKK? is a potential therapeutic target for Apc mutant colorectal cancer patients.

SUBMITTER: Colomer C

PROVIDER: S-EPMC5877427 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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IKKα is required in the intestinal epithelial cells for tumour stemness.

Colomer Carlota C Margalef Pol P Gonzalez Jessica J Vert Anna A Bigas Anna A Espinosa Lluis L

British journal of cancer 20180213 6

<h4>Background</h4>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.<h4>Methods</h4>We generated a compound mouse model with mutation in Apc and lacking intestinal epith ...[more]

PMID: 29438366

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Project description:Background & aimsSelf-renewal and multipotent differentiation are cardinal properties of intestinal stem cells (ISCs), mediated in part by WNT and NOTCH signaling. Although these pathways are well characterized, the molecular mechanisms that control the 'stemness' of ISCs are still not well defined. Here, we investigated the role of Krüppel-like factor 5 (KLF5) in regulating ISC functions.MethodsWe performed studies in adult Lgr5EGFP-IRES-creERT2;Rosa26LSLtdTomato (Lgr5Ctrl) and Lgr5EGFP-IRES-creERT2;Klf5fl/fl;Rosa26LSLtdTomato (Lgr5ΔKlf5) mice. Mice were injected with tamoxifen to activate Cre recombinase, which deletes Klf5 from the intestinal epithelium in Lgr5ΔKlf5 but not Lgr5Crtl mice. In experiments involving irradiation, mice were subjected to 12 Gy total body irradiation (TBI). Tissues were collected for immunofluorescence (IF) analysis and next generation sequencing. Oganoids were derived from fluoresecence activated cell sorted- (FACS-) single cells from tamoxifen-treated Lgr5ΔKlf5 or Lgr5Crtl mice and examined by immunofluorescence stain.ResultsLgr5+ ISCs lacking KLF5 proliferate faster than control ISCs but fail to self-renew, resulting in a depleted ISC compartment. Transcriptome analysis revealed that Klf5-null Lgr5+ cells lose ISC identity and prematurely differentiate. Following irradiation injury, which depletes Lgr5+ ISCs, reserve Klf5-null progenitor cells fail to dedifferentiate and regenerate the epithelium. Absence of KLF5 inactivates numerous selected enhancer elements and direct transcriptional targets including canonical WNT- and NOTCH-responsive genes. Analysis of human intestinal tissues showed increased levels of KLF5 in the regenerating epithelium as compared to those of healthy controls.ConclusionWe conclude that ISC self-renewal, lineage specification, and precursor dedifferentiation require KLF5, by its ability to regulate epigenetic and transcriptional activities of ISC-specific gene sets. These findings have the potential for modulating ISC functions by targeting KLF5 in the intestinal epithelium.

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IKK? is required in the intestinal epithelial cells for tumour stemness.

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IKKα is required in the intestinal epithelial cells for tumour stemness.

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