TY - JOUR
T1 - β-Catenin mutations as determinants of hepatoblastoma phenotypes in mice
AU - Zhang, Weiqi
AU - Meyfeldt, Jennifer
AU - Wang, Huabo
AU - Kulkarni, Sucheta
AU - Lu, Jie
AU - Mandel, Jordan A.
AU - Marburger, Brady
AU - Liu, Ying
AU - Gorka, Joanna E.
AU - Ranganathan, Sarangarajan
AU - Prochownik, Edward V.
N1 - Funding Information:
This work was supported by a Hyundai Hope on Wheels Scholar Grant (to E. V. P.) and NCI, National Institutes of Health, Grant RO1CA174713 (to E. V. P.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2019 Zhang et al.
PY - 2019/11/15
Y1 - 2019/11/15
N2 - 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 recurringβ-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 WTβ-catenin, are tumorigenic when co-expressed with a mutant form of yes-associated protein (YAP). However, tumor growth rates, histologies, nuclear-tocytoplasmic 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.
AB - 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 recurringβ-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 WTβ-catenin, are tumorigenic when co-expressed with a mutant form of yes-associated protein (YAP). However, tumor growth rates, histologies, nuclear-tocytoplasmic 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.
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U2 - 10.1074/jbc.RA119.009979
DO - 10.1074/jbc.RA119.009979
M3 - Article
C2 - 31597698
AN - SCOPUS:85075095258
VL - 294
SP - 17524
EP - 17542
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 46
ER -