Abstract
Abstract Intracellular iron homeostasis in normal cells is tightly regulated by the coordination of several proteins that are responsible for the uptake, intracellular storage, and removal of iron from cells. Cancer cells, including liver cancer cells, are characterized by profound abberations in intracellular iron metabolism. Dysregulated iron homeostasis has been found not only in rodent and human hepatocellular carcinomas, but also in several preneoplastic pathological states associated with liver cancer development; however, the precise mechanistic role of iron metabolic disturbances in the initiation and early progression of liver carcinogenesis has remained 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 characterized by a substantial decrease in the levels of cytoplasmic non-heme iron in initiated hepatocytes and altered expression of the major genes responsible for the proper maintenance of accurate intracellular homeostasis. Specifically, analysis of the gene expression patterns revealed prominent up-regulation of the ferroportin (Fpn) gene and down-regulation of the hepcidin (Hamp) gene in the preneoplastic livers. This indicates that the decreased intracellular levels of non-heme iron in preneoplastic foci may be attributed to increased iron export from the cells driven by the loss of an inhibitory effect of hepcidin on Fpn. This suggestion is supported by a substantial up-regulation of Fpn (3-fold) compared to transferrin receptor (Tfrc) gene, (1.6 fold), the latter of which is responsible for the iron intake into cell. These data indicate that in preneoplastic livers there is a disruption in the balance of regulatory networks controlling cellular iron uptake and export. Interestingly, we detected similar gene expression changes in initiated preneoplastic liver cells that were transformed by culturing of non-tumorigenic TRL-1215 rat liver cells in the presence of iron. 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 may affect liver cancer development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5556. doi:10.1158/1538-7445.AM2011-5556
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