title: Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutantβ-catenin.
abstract: Aberrant wnt/β-catenin signaling and amplification/overexpression of Myc are associated with hepatoblastoma (HB), the most prevalent type of childhood liver cancer. To address their roles in the pathogenesis of HB, we generated mice in which Myc and mutant β-catenin were targeted to immature cells of the developing mouse liver. Perinatal coexpression of both genes promoted the preferential development of HBs over other tumor types in neonatal mice, all of which bore striking resemblance to their human counterparts. Integrated analysis indicated that tumors emerged as a consequence of Myc-driven alterations in hepatoblast fate in a background of pan-hepatic injury, inflammation, and nuclear factor (erythroid-derived 2)-like 2/Nrf2-dependent antioxidant signaling, which was specifically associated with expression of mutant β-catenin but not Myc. Immunoprofiling of human HBs confirmed that approximately 50% of tumors demonstrated aberrant activation of either Myc or Nfe2l2/Nrf2, while knockdown of Nrf2 in a cell line-derived from a human HB withNFE2L2gene amplification reduced tumor cell growth and viability. Taken together, these data indicate that β-catenin creates a protumorigenic hepatic environment in part by indirectly activating Nrf2 and implicate oxidative stress as a possible driving force for a subset of β-catenin-driven liver tumors in children.
authors.affiliation: Department of Molecular Genetics and.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Comerford
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Hinnant
authors.affiliation: Department of Epidemiology and Biostatistics and.|Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Hima
authors.initials: H
authors.lastname: Bansal
authors.affiliation: Department of Molecular Genetics and.
authors.forename: Shawn
authors.initials: S
authors.lastname: Klapproth
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rakheja
authors.affiliation: Department of Pathology, and.
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Finegold
authors.affiliation: Department of Pathology, and.|Department of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA.
authors.forename: Dolores
authors.initials: D
authors.lastname: Lopez-Terrada
authors.affiliation: Department of Molecular Biology.|Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: O'Donnell
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.|Department of Pediatrics, University of Texas Health Science Center at San Antonio and Greehey Children's Cancer Research Institute, San Antonio, Texas, USA.
authors.forename: Gail E
authors.initials: GE
authors.lastname: Tomlinson
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D018197:Hepatoblastoma / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics*
chemical_list: C495267:CTNNB1 protein, mouse; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D051176:beta Catenin