Back to Search
Start Over
AXIN deficiency in human and mouse hepatocytes induces hepatocellular carcinoma in the absence of β-catenin activation
- Source :
- Journal of Hepatology, Journal of Hepatology, 2018, 68 (6), pp.1203-1213. ⟨10.1016/j.jhep.2017.12.018⟩, Journal of Hepatology, Elsevier, 2018, 68 (6), pp.1203-1213. ⟨10.1016/j.jhep.2017.12.018⟩, Journal of Hepatology, 2018, 68 (6), pp.1203-1213. 〈10.1016/j.jhep.2017.12.018〉
- Publication Year :
- 2018
- Publisher :
- HAL CCSD, 2018.
-
Abstract
- Background & Aims The Wnt/β-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/β-catenin signaling pathway, are observed in about 10% of HCCs. Whole-genome studies usually place HCC with AXIN1 mutations and CTNNB1 mutations in the group of tumors with Wnt/β-catenin activated program. However, it has been shown that HCCs with activating CTNNB1 mutations form a group of HCCs, with a different histology, prognosis and genomic signature to those with inactivating biallelic AXIN1 mutations. We aimed to elucidate the relationship between CTNNB1 mutations, AXIN1 mutations and the activation level of the Wnt/β-catenin program. Methods We evaluated two independent human HCC datasets for the expression of a 23-β-catenin target genes program. We modeled Axin1 loss of function tumorigenesis in two engineered mouse models and performed gene expression profiling. Results Based on gene expression, we defined three levels of β-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 β-catenin induction. We defined a 329-gene signature common in human and mouse AXIN1 mutated HCC that is highly enriched in Notch and YAP oncogenic signatures. Conclusions AXIN1 -mutated HCCs occur independently of the Wnt/β-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/β-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/β-catenin pathway.
- Subjects :
- Male
0301 basic medicine
Carcinoma, Hepatocellular
Carcinogenesis
[SDV.CAN]Life Sciences [q-bio]/Cancer
Biology
medicine.disease_cause
Mouse model
Mice
03 medical and health sciences
Liver Neoplasms, Experimental
Axin Protein
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
AXIN1
medicine
Animals
Humans
Wnt Signaling Pathway
neoplasms
beta Catenin
Tumor signature
Cancer
Mice, Knockout
Mutation
Receptors, Notch
[ SDV ] Life Sciences [q-bio]
Hepatology
Liver Neoplasms
Wnt signaling pathway
[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
HCCS
Prognosis
medicine.disease
digestive system diseases
3. Good health
Gene expression profiling
030104 developmental biology
Liver
Catenin
Hepatocytes
Cancer research
Subjects
Details
- Language :
- English
- ISSN :
- 01688278 and 16000641
- Database :
- OpenAIRE
- Journal :
- Journal of Hepatology, Journal of Hepatology, 2018, 68 (6), pp.1203-1213. ⟨10.1016/j.jhep.2017.12.018⟩, Journal of Hepatology, Elsevier, 2018, 68 (6), pp.1203-1213. ⟨10.1016/j.jhep.2017.12.018⟩, Journal of Hepatology, 2018, 68 (6), pp.1203-1213. 〈10.1016/j.jhep.2017.12.018〉
- Accession number :
- edsair.doi.dedup.....1a6ba3105ddc678d0e390666ba0d098b