Gas1-Mediated Suppression of Hepatoblastoma Tumorigenesis

Hepatoblastoma (HB), the most common pediatric liver cancer, is associated with dysregulated Wnt/β-catenin, Hippo, and/or nuclear factor erythroid 2 ligand 2/nuclear respiratory factor 2 (NFE2L2/NRF2) pathways. In mice, pairwise combinations of oncogenically active forms of the terminal transcription factors of these pathways, namely, β-catenin (B), Yes-associated protein (YAP; Y), and Nrf2 (N), generate HBs, 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. The identification of those most involved in transformation might reveal mechanisms and opportunities for therapy. Herein, transcription profiling of >60 murine HBs revealed a common set of 22 "BYN" genes similarly deregulated in all cases. Most were associated with multiple cancer hallmarks, and their expression often correlated with survival in HBs, hepatocellular carcinomas, and other cancers. Among the most down-regulated of these genes was Gas1, which encodes a glycosylphosphatidylinositol-linked outer membrane protein. The restoration of Gas1 expression impaired B + Y + N-driven HB tumor growth in vivo and in HB-derived immortalized BY and BYN cell lines in vitro in a manner that requires membrane anchoring of the protein via its glycosylphosphatidylinositol moiety, implicating Gas1 as a proximal mediator of HB pathogenesis and validating the BYN gene set as deserving of additional scrutiny in future studies.