Gas1-Mediated Suppression of Hepatoblastoma Tumorigenesis.

Abstract

Hepatoblastoma (HB), the most common pediatric liver cancer, often dysregulates the Wnt/β-catenin, Hippo and/or NFE2L2/NRF2 pathways. Pairwise combinations of oncogenically active forms of the terminal transcription factors of these pathways, namely β-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 of paramount importance as it might reveal new mechanistic insights and therapeutic opportunities. Transcriptional profiling of >60 murine HBs has previously revealed a common set of 22 "BYN genes" that are similarly deregulated in all cases. Most 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 BY and BYN cell lines in vitro in a manner than requires membrane anchoring of the protein via its GPI moiety. Our findings implicate Gas1 as a proximal mediator of HB pathogenesis and validate the BYN gene set as deserving of closer additional scrutiny in future studies.