title: Tumour promotion versus tumour suppression in chronic hepatic iron overload.
abstract: Although iron-catalysed oxidative damage is presumed to be a major mechanism of injury leading to cirrhosis and hepatocellular carcinoma in hemochromatosis, these events have been difficult to recapitulate in an animal model. In this study, we evaluated regulators of hepatocarcinogenesis in a rodent model of chronic iron overload. Sprague-Dawley rats were iron loaded with iron dextran over 6 months. Livers were harvested and analysed for markers of oxidative stress, as well as the following proteins: p53, murine double minute 2, the Shc proteins p66, p52, p46; β-catenin, CHOP, C/EBPα and Yes-associated protein. In this model, iron loading is associated with hepatocyte proliferation, and indices of oxidative damage are mildly increased in tandem with augmented antioxidant defenses. Alterations potentially favouring carcinogenesis included a modest but significant decrease in p53 levels and increases in p52, p46 and β-catenin levels compared with control livers. Countering these factors, the iron-loaded livers demonstrated a significant decrease in CHOP, which has recently been implicated in the development of hepatocellular carcinoma, as well as a reciprocal increase in C/EBPα and decrease in Yes-associated protein. Our results suggest that chronic iron overload elicits both tumour suppressive as well as tumour-promoting mechanisms in rodent liver.
authors.affiliation: Division of Science and Engineering, Penn State Abington College, Abington, PA, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Bloomer
authors.affiliation: Iowa City Veterans Administration Medical Center, Iowa City, IA, USA.|Division of Gastroenterology-Hepatology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.|Program in Free Radical and Radiation Biology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Kyle E
authors.initials: KE
authors.lastname: Brown
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002273:Carcinogens / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002471:Cell Transformation, Neoplastic; D002908:Chronic Disease; D007501:Iron / Q000008:administration & dosage*; D019190:Iron Overload / Q000150:complications* / Q000503:physiopathology; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D002273:Carcinogens; D025521:Tumor Suppressor Proteins; D007501:Iron
keywords: C/EBPα; CHOP; MDM2; Yes-associated protein; hemochromatosis; liver; oxidative stress; β-catenin