Hepatocyte dedifferentiation is a major source of hepatocellular carcinoma (HCC), but its mechanisms are unknown. We explored the p73 expression in HCC tumors and studied the effects of transcriptionally active p73β (TAp73β) in HCC cells. Expression profiles of p73 and patient clinical data were collected from the Genomic Data Commons (GDC) data portal and the TSVdb database, respectively. Global gene expression profiles were determined by pan-genomic 54K microarrays. The Gene Set Enrichment Analysis method was used to identify TAp73β-regulated gene sets. The effects of TAp73 isoforms were analyzed in monolayer cell culture, 3D-cell culture and xenograft models in zebrafish using western blot, flow cytometry, fluorescence imaging, real-time polymerase chain reaction (RT-PCR), immunohistochemistry and morphological examination. TAp73 isoforms were significantly upregulated in HCC, and high p73 expression correlated with poor patient survival. The induced expression of TAp73β caused landscape expression changes in genes involved in growth signaling, cell cycle, stress response, immunity, metabolism and development. Hep3B cells overexpressing TAp73β had lost hepatocyte lineage biomarkers including ALB, CYP3A4, AFP, HNF4α. In contrast, TAp73β upregulated genes promoting cholangiocyte lineage such as YAP, JAG1 and ZO-1, accompanied with an increase in metastatic ability. Our findings suggest that TAp73β may promote malignant dedifferentiation of HCC cells.

Department of Biostatistics and Medical Informatics Faculty of Medicine Ege University Izmir 35000 Turkey

Department of Medical Biology Faculty of Medicine Dokuz Eylul University Izmir 35000 Turkey

Department of Medical Biology Faculty of Medicine Karadeniz Technical University Trabzon 61000 Turkey

Izmir Biomedicine and Genome Center Izmir 35000 Turkey

Izmir Bozyaka Education and Research Hospital University of Health Sciences Izmir 35000 Turkey

Izmir International Biomedicine and Genome Institute Dokuz Eylul University Izmir 35000 Turkey

RECAMO Masaryk Memorial Cancer Institute 60200 Brno Czech Republic

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