Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant β-catenin
Sarah A. Comerford, … , Gail E. Tomlinson, Robert E. Hammer
Sarah A. Comerford, … , Gail E. Tomlinson, Robert E. Hammer
Published October 6, 2016
Citation Information: JCI Insight. 2016;1(16):e88549. https://doi.org/10.1172/jci.insight.88549.
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Research Article Hepatology Oncology

Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant β-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 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.

Authors

Sarah A. Comerford, Elizabeth A. Hinnant, Yidong Chen, Hima Bansal, Shawn Klapproth, Dinesh Rakheja, Milton J. Finegold, Dolores Lopez-Terrada, Kathryn A. O’Donnell, Gail E. Tomlinson, Robert E. Hammer

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Figure 4

Immunohistochemical profiling indicates that HBs from β-catΔEx3:Myc and Tet-O-Myc mice are ontogenically distinct.

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Immunohistochemical profiling indicates that HBs from β-catΔEx3:Myc and ...
Photomicrographs of immunohistochemistry (IHC) of WT livers and tumor-bearing livers of β-catΔEx3:Myc and Tet-O-Myc mice with antibodies specific for (A–C) HNF4α, (D–F) AFP, (G–I) DLK1, (J–L) GLUL, (M–O) PCNA, (P–R) CITED1, (S–U) LIN28A, (V–X) LIN28B, (Y–AA) EpCAM, and (BB–DD) SOX9. Hepatoblastomas (HBs) from both strains express the oncofetal genes AFP, DLK1, CITED1, and LIN28B but lack expression of SOX9 in all but a few tumor cells (arrows in CC and DD). Only embryonal HBs originating in Tet-O-Myc mice express LIN28A and EpCAM. Expression of AFP and GLUL in fetal HBs from β-catΔEx3:Myc mice is higher than in HBs from Tet-O-Myc mice, consistent with a higher degree of tumor cell differentiation in the fetal HBs. Note pericentral-restricted expression of GLUL (glutamine synthetase) in (J) normal and (L) tumor-adjacent liver in Tet-O-Myc mice, indicating maintenance of normal hepatic architecture and zonation in nontumorous liver. The arrow in M highlights a solitary PCNA-positive hepatocyte in liver from a WT mouse, in contrast to an abundance of PCNA-positive cells in HBs (N and O). Arrowheads in Y, BB, and DD indicate EpCAM-positive or SOX9-positive bile ducts in WT liver, respectively. PV, portal vein; CV, central vein. Dashed lines demarcate tumor boundaries. AEC chromagen (red), hematoxylin counterstain (blue). Scale bar: 50 μm. Original magnification for inset in A, ×240.