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J Biol Chem. 2019 Nov 15;294(46):17524-17542. doi: 10.1074/jbc.RA119.009979. Epub 2019 Oct 9.

β-Catenin mutations as determinants of hepatoblastoma phenotypes in mice.

Author information

1
Division of Hematology/Oncology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224.
2
Tsinghua University School of Medicine, Beijing 100084, China.
3
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
4
Department of Pathology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224.
5
Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213.
6
Division of Hematology/Oncology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15224 procev@chp.edu.
7
Department of Microbiology and Molecular Genetics, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213.
8
Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15232.

Abstract

Hepatoblastoma (HB) is the most common pediatric liver cancer. Although long-term survival of HB is generally favorable, it depends on clinical stage, tumor histology, and a variety of biochemical and molecular features. HB appears almost exclusively before the age of 3 years, is represented by seven histological subtypes, and is usually associated with highly heterogeneous somatic mutations in the catenin β1 (CTNNB1) gene, which encodes β-catenin, a Wnt ligand-responsive transcriptional co-factor. Numerous recurring β-catenin mutations, not previously documented in HB, have also been identified in various other pediatric and adult cancer types. Little is known about the underlying factors that determine the above HB features and behaviors or whether non-HB-associated β-catenin mutations are tumorigenic when expressed in hepatocytes. Here, we investigated the oncogenic properties of 14 different HB- and non-HB-associated β-catenin mutants encoded by Sleeping Beauty vectors following their delivery into the mouse liver by hydrodynamic tail-vein injection. We show that all β-catenin mutations, as well as WT β-catenin, are tumorigenic when co-expressed with a mutant form of yes-associated protein (YAP). However, tumor growth rates, histologies, nuclear-to-cytoplasmic partitioning, and metabolic and transcriptional landscapes were strongly influenced by the identities of the β-catenin mutations. These findings provide a context for understanding at the molecular level the notable biological diversity of HB.

KEYWORDS:

MYC proto-oncogene BHLH transcription factor (c-Myc); Warburg effect; Wnt pathway; beta-catenin (B-catenin); catenin beta1 (CTNNB1); glutaminolysis; glycolysis; hepatoblastoma (HB); oxidative phosphorylation; pediatric cancer; pyruvate dehydrogenase complex (PDC); yes-associated protein (YAP)

PMID:
31597698
PMCID:
PMC6873193
[Available on 2020-11-15]
DOI:
10.1074/jbc.RA119.009979

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