Iron overload and liver cancer

Hereditary hemochromatosis (HH) is an important risk factor for the development of hepatocellular carcinoma (HCC), one of the most frequent and devastating types of cancer (El-Serag, 2011). HH is characterized by excessive absorption of iron, which is accumulated in different organs, including the liver, inducing toxicity (Pietrangelo, 2010). As a consequence, HH patients are at increased risk of developing liver fibrosis, cirrhosis, and eventually HCC. It has been proposed that iron accumulation in hepatocytes promotes oxidative stress, cell death, and compensatory proliferation, which all together favor the accumulation of mutations in hepatocytes and subsequent malignant transformation (Fu and Chung, 2018). HH is in general caused by homozygous mutations in the homeostatic iron regulator (HFE) gene, which is involved in the tight regulation of iron absorption. Iron homeostasis is also regulated by F-box and leucine-rich repeat protein 5 (FBXL5) and iron regulatory protein 2 (IRP2; Moroishi et al., 2011). IRP2 is an RNA-binding protein that controls the production of proteins involved in iron accumulation while FBXL5 negatively regulates IRP2. While the increased risk of HCC development in patients with excessive iron accumulation is well established, the basic and translation aspects are understudied, in part due to the lack of faithful genetically engineered mouse models recapitulating iron overload and HCC development. In this study by Muto et al., a genetically engineered mouse model of HCC characterized by iron overload has been developed.