AXIN deficiency in human and mouse hepatocytes induces hepatocellular carcinoma in the absence of beta-catenin activation

Autor: Abitbol , Shirley, Dahmani , Rajae, Coulouarn , Cédric, Ragazzon , Bruno, Mlecnik , Bernhard, Senni , Nadia, Savall , Mathilde, Bossard , Pascale, Sohier , Pierre, Drouet , Valerie, Tournier , Emilie, Dumont , Florent, Sanson , Romain, Calderaro , Julien, Zucman-Rossi , Jessica, VASSEUR-COGNET , Mireille, Just , Pierre-Alexandre, Terris , Benoit, Perret , Christine, Gilgenkrantz , Helene
Přispěvatelé: Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Nutrition, Métabolismes et Cancer ( NuMeCan ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Inovarion, Génomique Fonctionnelle des Tumeurs Solides ( U1162 ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut d'écologie et des sciences de l'environnement de Paris ( IEES ), Institut National de la Recherche Agronomique ( INRA ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de recherche sur l'inflamation - UMR 1149, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), LNCC (Ligue Nationale Contre le Cancer), Association Francaise pour l'Etude du Foie (AFEF)
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Journal of Hepatology
Journal of Hepatology, Elsevier, 2018, 68 (6), pp.1203-1213. 〈10.1016/j.jhep.2017.12〉
ISSN: 0168-8278
Popis: International audience; Background and Aims The Wnt/beta-catenin pathway is the most frequently deregulated pathway in hepatocellular carcinoma (HCC). Inactivating mutations of the gene encoding AXIN1, a known negative regulator of the Wnt/beta-catenin signaling pathway, are observed in about 10% of HCCs. Whole-genome studies usually place HCC with AXINI mutations and CTNNBI mutations in the group of tumors with Wnt/beta-catenin activated program. However, it has been shown that HCCs with activating CTNNBI mutations form a group of HCCs, with a different histology, prognosis and genomic signature to those with inactivating biallelic AXINI mutations. We aimed to elucidate the relationship between CTNNBI mutations, AXINI mutations and the activation level of the Wnt/beta-catenin program. Methods We evaluated two independent human HCC datasets for the expression of a 23-beta-catenin target genes program. We modeled Axinl loss of function tumorigenesis in two engineered mouse models and performed gene expression profiling. Results Based on gene expression, we defined three levels of beta-catenin program activation strong, weak or no activation. While more than 80% CTNNB1-mutated tumors were found in the strong or in the weak activation program, most of the AXIN1-mutated tumors (>70%) were found in the subgroup with no activation. We validated this result by demonstrating that mice with a hepatocyte specific AXIN1 deletion developed HCC in the absence of beta-catenin induction. We defined a 329-gene signature common in human and mouse AXINI mutated HCC that is highly enriched in Notch and YAP oncogenic signatures. ConclusionsAXIN1-mutated HCCs occur independently of the Wnt/beta-catenin pathway and involve Notch and YAP pathways. These pathways constitute potentially interesting targets for the treatment of HCC caused by AXIN1 mutations. Lay summary Liver cancer has a poor prognosis. Defining the molecular pathways involved is important for developing new therapeutic approaches. The Wnt/beta-catenin pathway is the most frequently deregulated pathway in hepatocellular carcinoma (HCC). Mutations of AXIN1, a member of this pathway, represent about 10% of HCC mutations. Using both human HCC collections and engineered mouse models of liver cancers with AXIN1 mutation or deletion, we defined a common signature of liver tumors mutated for AXIN1 and demonstrate that these tumors occur independently of the activation of the Wnt/beta-catenin pathway. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Databáze: OpenAIRE
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