Axin1 Protects Colon Carcinogenesis by an Immune-Mediated Effect.

Autor:	Sanson R; Université de Paris, Institut Cochin, INSERM, Centre National Recherche Scientifique, Paris, France; Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France., Lazzara SL; Université de Paris, Institut Cochin, INSERM, Centre National Recherche Scientifique, Paris, France; Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France., Cune D; Université de Paris, Institut Cochin, INSERM, Centre National Recherche Scientifique, Paris, France; Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France., Pitasi CL; Université de Paris, Institut Cochin, INSERM, Centre National Recherche Scientifique, Paris, France; Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France., Trentesaux C; Université de Paris, Institut Cochin, INSERM, Centre National Recherche Scientifique, Paris, France; Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France., Fraudeau M; Université de Paris, Institut Cochin, INSERM, Centre National Recherche Scientifique, Paris, France; Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France., Letourneur F; Genomic Facility, Université de Paris, Institut Cochin, INSERM, Centre National Recherche Scientifique, Paris, France., Saintpierre B; Genomic Facility, Université de Paris, Institut Cochin, INSERM, Centre National Recherche Scientifique, Paris, France., Le Gall M; Proteomic Facility, Université de Paris, Institut Cochin, INSERM, Centre National Recherche Scientifique, Paris, France., Bossard P; Université de Paris, Institut Cochin, INSERM, Centre National Recherche Scientifique, Paris, France; Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France., Terris B; Université de Paris, Institut Cochin, INSERM, Centre National Recherche Scientifique, Paris, France; Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires Paris Centre, Pathology Department, Hôpital Cochin, Paris, France., Finetti P; Laboratory of Predictive Oncology, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, INSERM Unité Mixte de Recherche 1068, Centre National Recherche Scientifique Unité Mixte de Recherche 725, Marseille, France., Bertucci F; Laboratory of Predictive Oncology, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, INSERM Unité Mixte de Recherche 1068, Centre National Recherche Scientifique Unité Mixte de Recherche 725, Marseille, France., Mamessier E; Laboratory of Predictive Oncology, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, INSERM Unité Mixte de Recherche 1068, Centre National Recherche Scientifique Unité Mixte de Recherche 725, Marseille, France., Romagnolo B; Université de Paris, Institut Cochin, INSERM, Centre National Recherche Scientifique, Paris, France; Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France. Electronic address: beatrice.romagnolo@inserm.fr., Perret C; Université de Paris, Institut Cochin, INSERM, Centre National Recherche Scientifique, Paris, France; Equipe Labellisée Ligue Nationale Contre Le Cancer, Paris, France. Electronic address: christine.perret@inserm.fr.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2023; Vol. 15 (3), pp. 689-715. Date of Electronic Publication: 2022 Nov 08.
DOI:	10.1016/j.jcmgh.2022.10.017
Abstrakt:	Background & Aims: Axin1 is a negative regulator of wingless-type MMTV integration site family, member 1 (Wnt)/β-catenin signaling with tumor-suppressor function. The Wnt pathway has a critical role in the intestine, both during homeostasis and cancer, but the role of Axin1 remains elusive. Methods: We assessed the role of Axin1 in normal intestinal homeostasis, with control, epithelial-specific, Axin1-knockout mice (Axin1 ΔIEC ) and Axin2-knockout mice. We evaluated the tumor-suppressor function of Axin1 during chemically induced colorectal tumorigenesis and dextran sulfate sodium-induced colitis, and performed comparative gene expression profiling by whole-genome RNA sequencing. The clinical relevance of the Axin1-dependent gene expression signature then was tested in a database of 2239 clinical colorectal cancer (CRC) samples. Results: We found that Axin1 was dispensable for normal intestinal homeostasis and redundant with Axin2 for Wnt pathway down-regulation. Axin1 deficiency in intestinal epithelial cells rendered mice more susceptible to chemically induced colon carcinogenesis, but reduced dextran sulfate sodium-induced colitis by attenuating the induction of a proinflammatory program. RNA-seq analyses identified an interferon γ/T-helper1 immune program controlled by Axin1 that enhances the inflammatory response and protects against CRC. The Axin1-dependent gene expression signature was applied to human CRC samples and identified a group of patients with potential vulnerability to immune checkpoint blockade therapies. Conclusions: Our study establishes, in vivo, that Axin1 has redundant function with Axin2 for Wnt down-regulation and infers a new role for Axin1. Physiologically, Axin1 stimulates gut inflammation via an interferon γ/Th1 program that prevents tumor growth. Linked to its T-cell-mediated effect, the colonic Axin1 signature offers therapeutic perspectives for CRC. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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