PAGE4, upregulated in a novel iPSC-derived hepatoblastoma model, promotes hepatoblastoma progression
Hepatoblastoma is a primary malignant liver tumor in children, thought to arise from abnormal liver development during the fetal period. Approximately 90% of cases harbor activating mutations in CTNNB1, which encodes ß-catenin, while other genetic mutations are rare. Recent studies have shown that CTNNB1 mutations are frequently accompanied by increased expression of the transcriptional coactivator YAP, which promotes cell proliferation and suppresses apoptosis. Based on these findings, we established a hepatoblastoma model by introducing active forms of CTNNB1 and YAP into human iPSC-derived hepatoblasts. Cells transduced with both genes showed distinct morphological changes and upregulation of CTNNB1, YAP, and their downstream target genes. RNA-seq followed by Gene Set Enrichment Analysis (GSEA) revealed that the gene expression profile of these cells closely matches that of hepatoblastoma patients. Utilizing this model, we identified Prostate-Associated Gene 4 (PAGE4)  as a novel candidate gene involved in hepatoblastoma progression. Functional analysis in hepatoblastoma cell lines (Huh6, HepG2) demonstrated that PAGE4 plays a role in promoting cell proliferation and resistance to apoptosis. Since PAGE4 is a known cancer/testis antigen with tumor-specific expression, it has been recognized as a potential target in cancer therapy. Our findings indicate that PAGE4 represents a novel and promising therapeutic target for hepatoblastoma. Overall design: RNA-seq profiling of iPSC-derived human hepatoblasts and their Day 14 derivatives overexpressing CTNNB1, YAP, or both CTNNB1 and YAP.