Aberrant SOX9 expression mediated by protumour macrophages predicts poorer clinical outcomes in hepatoblastoma

Tumour-associated macrophages (TAMs) are known to promote tumour progression in many kinds of malignant tumour, including hepatoblastoma (HB). Based on previous studies, we suggested that TAM-mediated sex-determining region Y-box 9 (SOX9) signal might enhance HB progression. The present study investigated the significance of the SOX9 signal in HB and examined the mechanisms underlying cell-cell interactions between tumour cells and TAMs. Co-culture with human monocyte-derived macrophages increased SOX9 expression in HB cell lines. Immunohistochemical analysis of HB samples revealed a positive correlation between SOX9 expression and TAM infiltration, and SOX9 expression was predominantly observed in the embryonal subtype. Increased SOX9 expression was associated with shorter 5-year recurrence-free and overall survival. Yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) signalling was found to be involved in macrophage-induced SOX9 upregulation. The Wnt/β-catenin pathway was also activated by co-culture with macrophages and appeared to be upregulated by SOX9 expression. In summary, SOX9 was identified as a poor prognostic factor in HB, with expression enhanced by macrophage-derived factors. The YAP/TAZ and Wnt/β-catenin pathways are critical for cell-cell communication and are linked to SOX9 overexpression. © 2026 The Pathological Society of Great Britain and Ireland.