title: Chronic administration of 2-acetylaminofluorene alters the cellular iron metabolism in rat liver.
abstract: Dysregulated intracellular iron homeostasis has been found not only in rodent and human hepatocellular carcinomas but also in several preneoplastic pathological states associated with hepatocarcinogenesis; however, the precise underlying mechanisms of metabolic iron disturbances in preneoplastic liver and the role of these disturbances remain unexplored. In the present study, using an in vivo model of rat hepatocarcinogenesis induced by 2-acetylaminofluorene, we found extensive alterations in cellular iron metabolism at preneoplastic stages of liver carcinogenesis. These were characterized by a substantial decrease in the levels of cytoplasmic non-heme iron in foci of initiated hepatocytes and altered expression of the major genes responsible for the proper maintenance of intracellular iron homeostasis. Gene expression analysis revealed that the decreased intracellular levels of iron in preneoplastic foci might be attributed to increased iron export from the cells, driven by upregulation of ferroportin (Fpn1), the only known non-heme iron exporter. Likewise, increased Fpn1 gene expression was found in vitro in TRL1215 rat liver cells with an acquired malignant phenotype, suggesting that upregulation of Fpn1 might be a specific feature of neoplastically transformed cells. Other changes observed in vivo included the downregulation of hepcidin (Hamp) gene, a key regulator of Fpn1, and this was accompanied by decreased levels of CCAAT/enhancer binding proteins alpha and beta, especially at the Hamp promoter. In conclusion, our results demonstrate the significance of altered intracellular iron metabolism in the progression of liver carcinogenesis and suggest that correction of these alterations could possibly affect liver cancer development.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079, USA.
authors.forename: Svitlana I
authors.initials: SI
authors.lastname: Shpyleva
authors.forename: Levan
authors.initials: L
authors.lastname: Muskhelishvili
authors.forename: Volodymyr P
authors.initials: VP
authors.lastname: Tryndyak
authors.forename: Igor
authors.initials: I
authors.lastname: Koturbash
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Tokar
authors.forename: Michael P
authors.initials: MP
authors.lastname: Waalkes
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Beland
authors.forename: Igor P
authors.initials: IP
authors.lastname: Pogribny
mesh_terms: D015073:2-Acetylaminofluorene / Q000633:toxicity*; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000378:metabolism; D002273:Carcinogens / Q000633:toxicity*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D064451:Hepcidins; D006706:Homeostasis / Q000187:drug effects; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D008297:Male; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D002273:Carcinogens; D027682:Cation Transport Proteins; C578702:HAMP protein, human; C578703:Hamp protein, rat; D064451:Hepcidins; D000098742:Ferroportin; D015073:2-Acetylaminofluorene; D007501:Iron