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Tumour promotion versus tumour suppression in chronic hepatic iron overload
Author(s) -
Bloomer Steven A.,
Brown Kyle E.
Publication year - 2015
Publication title -
cell biochemistry and function
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.933
H-Index - 61
eISSN - 1099-0844
pISSN - 0263-6484
DOI - 10.1002/cbf.3110
Subject(s) - oxidative stress , hepatocellular carcinoma , hemochromatosis , hereditary hemochromatosis , cirrhosis , carcinogenesis , medicine , hepatocyte , endocrinology , ferroportin , cancer research , chop , biology , cancer , hepcidin , biochemistry , chemotherapy , anemia , in vitro
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/EBP α 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/EBP α 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. Copyright © 2015 John Wiley & Sons, Ltd.