Abstract
Hepatoblastoma is the most common malignant pediatric liver cancer. Histological evaluation of tumor biopsies is used to distinguish among the different subtypes of hepatoblastoma, with fetal and embryonal representing the two main epithelial components. With frequent CTNNB1 mutations, hepatoblastoma is a Wnt/β‐catenin‐driven malignancy. Considering that Wnt activation has been associated with tumor metabolic reprogramming, we characterized the metabolic profile of cells from hepatoblastoma and compared it to cells from hepatocellular carcinoma. First, we demonstrated that glucose transporter GLUT3 is a direct TCF4/β‐catenin target gene. RNA sequencing enabled to identify molecular and metabolic features specific to hepatoblastoma and revealed that several glycolytic enzymes are overexpressed in embryonal‐like compared to fetal‐like tumor cells. This led us to implement successfully three biomarkers to distinguish embryonal from fetal components by immunohistochemistry from a large panel of human hepatoblastoma samples. Functional analyses demonstrated that embryonal‐like hepatoblastoma cells are highly glycolytic and sensitive to hexokinase‐1 silencing. Altogether, our findings reveal a new, metabolic classification of human hepatoblastoma, with potential future implications for patients’ diagnosis and treatment.
Highlights
Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the first and the second most common pediatric malignant liver tumors representing about 1–2% of cancers in children
In an effort to comprehend molecular differences between two cancers that originate from the same tissue, HCC and HB, we profiled four HCC (Huh-1, Hep3B, HLE, and HLF) and four HB (HepU2, Huh-6, HepG2, and Hep293TT) cell lines using RNA sequencing (RNAseq)
We recently reported that SLC2A3 encoding for GLUT3 is induced by ZEB1 during epithelial–mesenchymal transition (EMT) in tumor cells from non-small cell lung cancer (NSCLC) and HCC (Masin et al, 2014)
Summary
Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the first and the second most common pediatric malignant liver tumors representing about 1–2% of cancers in children. In HB, large deletions in CTNNB1, which encompass exon 3 and part of exon 4, were reported exclusively in pure fetal tumor histotypes, whereas CTNNB1 mutations in embryonal HB are small mutations confined to exon 3 (LopezTerrada et al, 2009). It is unclear whether and how different deletions affect b-catenin activity, the differential gene expression profiles in HB subtypes raise the possibility of context and time-dependent activation of b-catenin, leading to enriched expression of Wnt and stem cell-related genes in embryonal tumors, and activation of hepatic differentiation program in fetal tumors (Cairo et al, 2008; Lopez-Terrada et al, 2009).
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