title: Nuclear receptor CAR-regulated expression of the FAM84A gene during the development of mouse liver tumors.
abstract: The nuclear xenobiotic receptor CAR is a phenobarbital (PB)-activated transcription factor. Using a mouse model of two-step liver tumorigenesis, in which tumor growth was initiated by diethyl nitrosamine (DEN) and promoted by chronic treatment with PB, we previously demonstrated that tumors developed only in the presence of CAR. Here, we have identified the FAM84A (family with sequence similarity 84, member A) gene as a CAR-regulated gene that is over-expressed during development of phenobarbital-promoted mouse liver tumors. FAM84A mRNA was induced in the liver of DEN/PB-treated mice prior to the development of liver tumors and this induction continued in the non-tumor as well as tumor tissues of a tumor-bearing liver. Western blotting demonstated that FAM84A protein expression increased in mouse liver after PB treatment; however, the FAM84A protein in liver and liver tumors was not phosphorylated at the serine 38 residue, which has been reported to correlate with morphological changes in cells. Immunohistochemistry analysis revealed the cytoplasmic localization of FAM84A protein and its expression during tumor development in normal tissues (especially in hepatocytes around the central vein), eosinophilic foci, adenomas and carcinomas. HepG2 cell-based reporter assays indicated that CAR activated the FAM84A promoter. Exogenous over-expression of FAM84A in HepG2 cells resulted in increased cell migration. The physiological function of FAM84A remains unknown, but our results suggest that FAM84A is up-regulated by CAR during the development of liver tumors, and may play an important role in the progression of liver cancer by increasing cell migration.
authors.affiliation: Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kamino
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yamazaki
authors.forename: Kosuke
authors.initials: K
authors.lastname: Saito
authors.forename: Daichi
authors.initials: D
authors.lastname: Takizawa
authors.forename: Satoru
authors.initials: S
authors.lastname: Kakizaki
authors.forename: Rick
authors.initials: R
authors.lastname: Moore
authors.forename: Masahiko
authors.initials: M
authors.lastname: Negishi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D000090702:Constitutive Androstane Receptor; D004195:Disease Models, Animal; D005260:Female; D018757:GABA Modulators / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D010634:Phenobarbital / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012737:Sex Factors
chemical_list: D000090702:Constitutive Androstane Receptor; D018757:GABA Modulators; D009363:Neoplasm Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D010634:Phenobarbital