Mutant <i>CTNNB1</i> and histological heterogeneity define metabolic subtypes of hepatoblastoma.
Details
State: Public
Version: Final published version
Serval ID
serval:BIB_ABF970C7CD17
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mutant <i>CTNNB1</i> and histological heterogeneity define metabolic subtypes of hepatoblastoma.
Journal
EMBO molecular medicine
ISSN
1757-4684 (Electronic)
ISSN-L
1757-4676
Publication state
Published
Issued date
11/2017
Peer-reviewed
Oui
Volume
9
Number
11
Pages
1589-1604
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
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 <i>CTNNB1</i> 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 <i>GLUT3</i> 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.
Keywords
Carcinoma, Hepatocellular/metabolism, Carcinoma, Hepatocellular/pathology, Cell Line, Tumor, Child, Fetus/metabolism, Gluconeogenesis/genetics, Glucose Transporter Type 3/metabolism, Glycolysis/genetics, Hepatoblastoma/metabolism, Hepatoblastoma/pathology, Hexokinase/antagonists & inhibitors, Hexokinase/genetics, Hexokinase/metabolism, Humans, Liver Neoplasms/metabolism, Liver Neoplasms/pathology, Mutation, Proto-Oncogene Proteins c-myc/antagonists & inhibitors, Proto-Oncogene Proteins c-myc/genetics, Proto-Oncogene Proteins c-myc/metabolism, RNA Interference, RNA, Small Interfering/metabolism, Transcription Factor 4/genetics, Transcription Factor 4/metabolism, beta Catenin/antagonists & inhibitors, beta Catenin/genetics, beta Catenin/metabolism, glucose transporter, glycolysis, mutant β‐catenin, pediatric liver cancer
Pubmed
Web of science
Open Access
Yes
Create date
05/10/2017 9:18
Last modification date
20/08/2019 16:15