Gas1-Mediated Suppression of Hepatoblastoma Tumorigenesis

Abstract

Background and AimsHepatoblastoma (HB), the most common pediatric liver cancer, often dysregulates the Wnt/{beta}-catenin, Hippo and NFE2L2/NRF2 pathways. Pairwise combinations of oncogenically active forms of the terminal transcription factor effectors of these pathways, namely {beta}-catenin (B), YAP (Y) and NRF2 (N) generate HBs in mice, with the triple combination (B+Y+N) being particularly potent. Each tumor group alters the expression of thousands of B-,Y- and N-driven unique and common target genes. Identifying those most responsible for transformation is thus an important question as it might reveal new mechanistic insights and therapeutic opportunities. Approach and ResultsTranscriptional profiling of >60 murine HBs driven by the above oncogenic combinations and different B mutants and in genetic backgrounds that impair tumor growth rates but not initiation has revealed a common set of 22 "BYN genes" that are similarly deregulated in all cases. Many are associated with multiple "Cancer Hallmarks" and their expression levels often correlate with survival in human HBs, hepatocellular carcinomas and other cancers. Among the most down-regulated of these is Gas1, which encodes a Glycosylphosphatidylinositol (GPI)-linked outer membrane protein. We show here that restoring Gas1 expression impairs B+Y+N-driven HB tumor growth in vivo and in HB-derived immortalized cell lines in vitro in a manner than requires membrane anchoring of the protein via its GPI moiety. ConclusionsOur findings implicate Gas1 as a proximal mediator of HB pathogenesis and validate the BYN gene set as one deserving of closer additional scrutiny in future studies.