Genomic Profiling Reveals Unique Molecular Alterations in Hepatoblastomas and Adjacent Hepatocellular Carcinomas in B6C3F1 Mice.
The cell of origin of hepatoblastoma (HB) in humans and mice is unknown; it is hypothesized to be a transformed hepatocyte, oval cell, or hepatic progenitor cell. In mice, current dogma is that HBs arise from preexisting hepatocellular neoplasms as a result of further neoplastic transformation. However, there is little evidence supporting this direct relationship. To better understand the relationship between hepatocellular carcinoma (HCC) and HB and determine molecular similarities between mouse and human HB, global gene expression analysis and targeted mutation analysis were performed using HB, HCC, and adjacent liver from the same animals in a recent National Toxicology Program bioassay. There were significant differences in Hras and Ctnnb1 mutation spectra, and by microarray, HBs showed dysregulation of embryonic development, stem cell pluripotency, and genomic imprinting compared to HCC. Meta-analysis showed similarities between HB, early mouse embryonic liver, and hepatocyte-derived stem/progenitor cells compared to HCC. Our data show that there are striking differences between HB and HCC and suggest that HB is a significantly different entity that may arise from a hepatic precursor cell. Furthermore, mouse HB is similar to the human disease at the pathway level and therefore is likely a relevant model for evaluating human cancer hazard.
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Sachin
S
Bhusari
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA Experimental Pathology Laboratories, Research Triangle Park, North Carolina, USA.
Arun R
AR
Pandiri
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Hiroaki
H
Nagai
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Yu
Y
Wang
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Julie
J
Foley
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Hue-Hua L
HH
Hong
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Thai-Vu
TV
Ton
Toxicology Branch, Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Michael
M
DeVito
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Keith R
KR
Shockley
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Shyamal D
SD
Peddada
Molecular Genomics Core, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Kevin E
KE
Gerrish
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
David E
DE
Malarkey
Program Operations Branch, Division of the National Toxicology Program, Research Triangle Park, North Carolina, USA.
Michelle J
MJ
Hooth
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA.
Robert C
RC
Sills
Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA hoenerho@med.umich.edu.
Mark J
MJ
Hoenerhoff
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D023281:Genomics / Q000379:methods*; D018197:Hepatoblastoma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000737:chemistry; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D057089:Pathology, Molecular; D014116:Toxicology
carcinogenesis; genomics; liver; microarray; molecular pathology; rodent pathology; toxicologic pathology