Iron metabolism in a mouse model of hepatocellular carcinoma

Background & Aims: Liver cancer is the sixth most frequently diagnosed type of cancer and the third leading cause of cancer-related mortality worldwide. One of the most frequently effected pathways in liver carcinoma is the p53 signalling pathway. Emerging evidence indicates that deregulation of p53 leads to several metabolic disorders that are pivotal during cancer progression. Methods: We induced chronic liver disease and subsequent liver carcinoma formation by chronic injection of CCl4 (16 weeks treatment) in p53f/f and p53LKO mice. We characterized major differences between HCC from p53f/f and HCC from p53LKO mice. In addition, we characterized differences between HCC and ICC, both from p53LKO mice. Results: We show that Conclusions: Dysregulation of Notch signaling is involved in tumor differentiation. Loss of Rbpj triggers the formation of combined HCC-iCCA which is associated by a pro-tumorigenic environment. Results: We show that all liver cancers that develop on a p53-deficient background have an iron-poor phenotype with a “low hepcidin and high Tfr1” signature, while iron deficiency at the systemic level is restricted to female mice. In addition to iron, liver tumorigenesis correlated with significant deficits of selenium, zinc and manganese, accompanied by changes in their key metabolic players. Conclusions: Our work demonstrates a pivotal role for p53 in a complex network controlling tumor development and micronutrient metabolism, locally in the liver cancers, and at a systemic level along with highlighting sex-specific differences underlying liver cancer development and the distribution of trace elements. Total RNA was isolated from murine liver carcinoma, and the quality was analyzed by a bioanalyzer. Agilent Mouse Gene Expression Microarrays 8x60K were used.