TY - JOUR
T1 - Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant β-catenin
AU - Comerford, Sarah A.
AU - Hinnant, Elizabeth A.
AU - Chen, Yidong
AU - Bansal, Hima
AU - Klapproth, Shawn
AU - Rakheja, Dinesh
AU - Finegold, Milton J.
AU - Lopez-Terrada, Dolores
AU - O’Donnell, Kathryn A.
AU - Tomlinson, Gail E.
AU - Hammer, Robert E.
N1 - Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.
PY - 2016/10/6
Y1 - 2016/10/6
N2 - 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 with NFE2L2 gene 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.
AB - 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 with NFE2L2 gene 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.
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U2 - 10.1172/jci.insight.88549
DO - 10.1172/jci.insight.88549
M3 - Article
C2 - 27734029
AN - SCOPUS:85055605227
SN - 2379-3708
VL - 1
JO - JCI Insight
JF - JCI Insight
IS - 16
M1 - e88549
ER -