TAp73β Can Promote Hepatocellular Carcinoma Dedifferentiation

Iscan E., Ekin U., Yildiz G., Oz O., Keles U., Suner Karakülah A., ...Daha Fazla

CANCERS, sa.4, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Basım Tarihi: 2021
  • Doi Numarası: 10.3390/cancers13040783
  • Dergi Adı: CANCERS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, CINAHL, EMBASE, Veterinary Science Database, Directory of Open Access Journals
  • Anahtar Kelimeler: TAp73, hepatocellular carcinoma, metastasis, dedifferentiation, zebrafish, yes-associated protein 1
  • Dokuz Eylül Üniversitesi Adresli: Evet

Özet

Simple Summary Hepatocellular carcinoma (HCC) is a highly complex and heterogeneous type of cancer. Hepatocyte dedifferentiation is one of the important steps in the development of HCC. However, its molecular mechanisms are not well known. In this study, we report that transcriptionally active TAp73 isoforms are overexpressed in HCC. We also show that TAp73 beta suppresses the expression of the hepatocyte markers including CYP3A4, AFP, ALB, HNF4 alpha, while increasing the expression of several cholangiocyte markers in HCC cell lines. In conclusion, this report reveals a pro-oncogenic role for TAp73 beta in liver cancer. 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 p73 beta (TAp73 beta) 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 TAp73 beta-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 TAp73 beta caused landscape expression changes in genes involved in growth signaling, cell cycle, stress response, immunity, metabolism and development. Hep3B cells overexpressing TAp73 beta had lost hepatocyte lineage biomarkers including ALB, CYP3A4, AFP, HNF4 alpha. In contrast, TAp73 beta upregulated genes promoting cholangiocyte lineage such as YAP, JAG1 and ZO-1, accompanied with an increase in metastatic ability. Our findings suggest that TAp73 beta may promote malignant dedifferentiation of HCC cells.