Molecular Diagnostics | Published:

IKKα is required in the intestinal epithelial cells for tumour stemness

British Journal of Cancer volume 118, pages 839846 (20 March 2018) | Download Citation

Subjects

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-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.

Methods:

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.

Results:

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.

Conclusions:

IKKα is a potential therapeutic target for Apc mutant colorectal cancer patients.

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Change history

  • Corrected online 20 March 2018

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Acknowledgements

We thank Manolis Pasparakis for providing the IKKαlox mice, Sarah Bonnin from the CRG Genomics Unit for expert help and advice regarding sequencing and data analysis and Kitty van Zwieten for technical support. This work was supported by Fondo de Investigación Sanitaria, ISCIII (Grants PI16/00437 and PIE15/00008), Fundació la Marató de TV3 (Grant 20131210) and Agència de Gestió Ajuts Universitaris de Recerca (SGR 9015-356014/2017).

Author contributions

CC and PM performed the experiments and wrote the manuscript. JG and AV performed experiments. AB and LE designed the experiments and wrote the manuscript.

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Affiliations

  1. Cancer Research Program, Institut Mar d’Investigacions Mèdiques, CIBERONC, Hospital del Mar, Doctor Aiguader 88, 08003 Barcelona, Spain

    • Carlota Colomer
    • , Pol Margalef
    • , Jessica Gonzalez
    • , Anna Vert
    • , Anna Bigas
    •  & Lluis Espinosa
  2. DSB Repair Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK

    • Pol Margalef

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Lluis Espinosa.

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DOI

https://doi.org/10.1038/bjc.2017.459

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