Zhang W, Meyfeldt J, Wang H, Kulkarni S, Lu J, Mandel JA, Marburger B, Liu Y, Gorka JE, Ranganathan S, Prochownik EV. Î²-Catenin mutations as determinants of hepatoblastoma phenotypes in mice. J Biol Chem. 2019 Oct 9. pii: jbc.RA119.009979. doi: 10.1074/jbc.RA119.009979. PubMed PMID: 31597698.
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 Î²1 (CTNNB1) gene, which encodes Î²-catenin, a Wnt ligand-responsive transcriptional co-factor. Numerous recurring Î²-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 Î²-catenin mutations are tumorigenic when expressed in hepatocytes. Here, we investigated the oncogenic properties of 14 different HB- and non-HB-associated Î²-catenin mutants encoded by Sleeping Beauty vectors following their delivery into the mouse liver by hydrodynamic tail-vein injection. We show that all Î²-catenin mutations, as well as WT Î²-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 Î²-catenin mutations. These findings provide a context for understanding at the molecular level the notable biological diversity of HB.
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