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 5

Strategy to identify tumor-enriched and β-catenin–regulated hepatic genes.

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Strategy to identify tumor-enriched and β-catenin–regulated hepatic gene...
(A and B) Schematic showing strategy to identify differentially expressed genes (DEGs). (A) Total RNA isolated from livers of 4 WT, 3 β-catΔEx3, and 4 tumor-bearing β-catΔEx3:Myc mice was profiled using Agilent SurePrint mouse arrays. (B) Pairwise comparisons used to generate lists of β-catenin– (red) and β-catenin– and c-Myc–coregulated genes (green). Tumor-enriched DEGs (yellow) were identified by comparing profiles obtained from β-catΔEx3 livers, which never developed tumors, with those from tumor-bearing β-catΔEx3:Myc livers. The Venn diagram shows the number of unique and overlapping mRNAs identified within and between groups. (C) Multidimensional scaling (MDS) plot depicting the relationship among the transcriptional profiles of WT, β-catΔEx3, and β-catΔEx3:Myc livers. Note that β-catΔEx3 and β-catΔEx3:Myc profiles are similar to one another due to common expression of the mutant β-catenin allele. (D) Heatmap depicting hierarchical clustering of DEGs in livers of WT (blue), β-catΔEx3 (red), and β-catΔEx3:Myc (green) mice.