title: Global gene profiling of spontaneous hepatocellular carcinoma in B6C3F1 mice: similarities in the molecular landscape with human liver cancer.
abstract: Hepatocellular carcinoma (HCC) is an important cause of morbidity and mortality worldwide. Although the risk factors of human HCC are well known, the molecular pathogenesis of this disease is complex, and in general, treatment options remain poor. The use of rodent models to study human cancer has been extensively pursued, both through genetically engineered rodents and rodent models used in carcinogenicity and toxicology studies. In particular, the B6C3F1 mouse used in the National Toxicology Program (NTP) two-year bioassay has been used to evaluate the carcinogenic effects of environmental and occupational chemicals, and other compounds. The high incidence of spontaneous HCC in the B6C3F1 mouse has challenged its use as a model for chemically induced HCC in terms of relevance to the human disease. Using global gene expression profiling, we identify the dysregulation of several mediators similarly altered in human HCC, including re-expression of fetal oncogenes, upregulation of protooncogenes, downregulation of tumor suppressor genes, and abnormal expression of cell cycle mediators, growth factors, apoptosis regulators, and angiogenesis and extracellular matrix remodeling factors. Although major differences in etiology and pathogenesis remain between human and mouse HCC, there are important similarities in global gene expression and molecular pathways dysregulated in mouse and human HCC. These data provide further support for the use of this model in hazard identification of compounds with potential human carcinogenicity risk, and may help in better understanding the mechanisms of tumorigenesis resulting from chemical exposure in the NTP two-year carcinogenicity bioassay.
authors.affiliation: Cellular and Molecular Pathology Branch, National Institute of Environmental Health Science, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA. hoenerhm@niehs.nih.gov
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Hoenerhoff
authors.forename: Arun R
authors.initials: AR
authors.lastname: Pandiri
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Lahousse
authors.forename: Hu-Hua
authors.initials: HH
authors.lastname: Hong
authors.forename: Tai-Vu
authors.initials: TV
authors.lastname: Ton
authors.forename: Tiwanda
authors.initials: T
authors.lastname: Masinde
authors.forename: Scott S
authors.initials: SS
authors.lastname: Auerbach
authors.forename: Kevin
authors.initials: K
authors.lastname: Gerrish
authors.forename: Pierre R
authors.initials: PR
authors.lastname: Bushel
authors.forename: Keith R
authors.initials: KR
authors.lastname: Shockley
authors.forename: Shyamal D
authors.initials: SD
authors.lastname: Peddada
authors.forename: Robert C
authors.initials: RC
authors.lastname: Sills
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D015197:Carcinogenicity Tests / Q000379:methods; D002273:Carcinogens / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002453:Cell Cycle; D019295:Computational Biology; D030541:Databases, Genetic; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D056726:Genetic Association Studies / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009857:Oncogenes; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D002273:Carcinogens; D014157:Transcription Factors