Abstract
Chronic HBV infection is a major cause of hepatocellular carcinoma (HCC) worldwide. The phenotypes of HCC are diverse, in part, due to mutations in distinct oncogenes and/or tumor suppressor genes. These genetic drivers of HCC development have generally been considered as major mediators of tumor heterogeneity. Using the liver-specific Pten-null HBV transgenic mouse model of chronic viral infection, a critical role for liver lobule zone-specific gene expression patterns in determining HCC phenotype and β-catenin-dependent HBV biosynthesis is demonstrated. These observations suggest that the position of the hepatocyte within the liver lobule, and hence its intrinsic gene expression pattern at the time of cellular transformation, make critical contributions to the properties of the resulting liver tumor. These results may explain why therapies targeting pathways modulated by specific identified tumor driver genes display variable treatment efficacy.
Keywords:
Hepatitis B virus (HBV); Hepatocellular carcinoma (HCC); Liver lobule zonation; Phosphatase and tensin homolog (Pten); β-catenin (Ctnnb1).
Copyright © 2021 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Carcinoma, Hepatocellular / genetics*
-
Carcinoma, Hepatocellular / metabolism
-
Carcinoma, Hepatocellular / pathology
-
Carcinoma, Hepatocellular / virology
-
Cell Transformation, Neoplastic / genetics*
-
Cell Transformation, Neoplastic / metabolism
-
Female
-
Gene Expression Regulation, Neoplastic
-
Genetic Heterogeneity
-
Hepatitis B / genetics*
-
Hepatitis B / metabolism
-
Hepatitis B / pathology
-
Hepatitis B / virology
-
Hepatitis B virus / genetics*
-
Hepatitis B virus / metabolism
-
Hepatitis B virus / pathogenicity
-
Hepatocytes / metabolism*
-
Hepatocytes / virology
-
Hepcidins / genetics
-
Hepcidins / metabolism
-
Humans
-
Intercellular Signaling Peptides and Proteins / genetics
-
Intercellular Signaling Peptides and Proteins / metabolism
-
Lipocalin-2 / genetics
-
Lipocalin-2 / metabolism
-
Liver / metabolism
-
Liver / virology
-
Liver Neoplasms / genetics*
-
Liver Neoplasms / metabolism
-
Liver Neoplasms / pathology
-
Liver Neoplasms / virology
-
Male
-
Mice
-
Mice, Transgenic
-
Ornithine-Oxo-Acid Transaminase / genetics
-
Ornithine-Oxo-Acid Transaminase / metabolism
-
PTEN Phosphohydrolase / deficiency
-
PTEN Phosphohydrolase / genetics
-
Phenotype
-
Signal Transduction
-
T-Box Domain Proteins / genetics
-
T-Box Domain Proteins / metabolism
-
Virus Replication
-
beta Catenin / genetics*
-
beta Catenin / metabolism
Substances
-
CTNNB1 protein, mouse
-
Hamp protein, mouse
-
Hepcidins
-
Intercellular Signaling Peptides and Proteins
-
Lect2 protein, mouse
-
Lipocalin-2
-
T-Box Domain Proteins
-
Tbx3 protein, mouse
-
beta Catenin
-
Lcn2 protein, mouse
-
Ornithine-Oxo-Acid Transaminase
-
PTEN Phosphohydrolase
-
Pten protein, mouse